CNKSR2

Chr XX-linked

connector enhancer of kinase suppressor of Ras 2

Also known as: CNK2, KSR2, MAGUIN, MRXSHG

NCBI Gene: 22866 ENSG00000149970 UniProt: Q8WXI2 OMIM: 300724

This protein functions as a scaffold protein that mediates mitogen-activated protein kinase pathways downstream from Ras and may regulate synaptic protein assembly at the postsynaptic membrane. Mutations cause X-linked syndromic intellectual developmental disorder (Houge type), inherited in an X-linked pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Houge typeMIM #301008

X-linked

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · X-linked complex neurodevelopmental disorder · XL · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 5.57

OE 0.07 (0.03–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.61Z-score

OE missense 0.47 (0.42–0.54)

177 obs / 372.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.18)

0≤0.351.4

Missense OE?0.47 (0.42–0.54)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 3 / 41.9Missense obs/exp: 177 / 372.9Syn Z: 1.52

Background carrier burden — how many people carry a rare variant somewhere in CNKSR2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

549 rare PASS variants

Rare truncating (LoF)

1 in 2,900

45 rare PASS variants

Rare synonymous (reference)

1 in 190

305 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CNKSR2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 220	1 in 4,200
South Asian	~36k	1 in 110	1 in 4,700
Remaining (unassigned)	~31k	1 in 280	1 in 3,600
European (Finnish)	~27k	1 in 490	1 in 1,100
Admixed American	~23k	1 in 170	1 in 1,800
African / African American	~21k	1 in 180	≈ 1 in 6,100
East Asian	~20k	1 in 250	≈ 1 in 5,200
Ashkenazi Jewish	~13k	1 in 1,600	none seen
Middle Eastern	~2,758	1 in 250	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 22 coding exons well covered in gnomAD exomes; exons 4, 5, 7, 8, 16 and 3 more marginal. Genomes: all 22.? see exons ↓