KREMEN2

Chr 16

kringle containing transmembrane protein 2

Also known as: KRM2

NCBI Gene: 79412 ENSG00000131650 UniProt: Q8NCW0 OMIM: 609899

This gene encodes a transmembrane receptor for Dickkopf proteins that cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting endocytosis of Wnt receptors LRP5 and LRP6, playing important roles in limb development and bone formation regulation. Mutations in KREMEN2 cause autosomal recessive ectodermal dysplasia with syndactyly. The gene shows tolerance to loss-of-function variants (LOEUF 0.917), suggesting that complete loss of function may be required for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor. A similar protein in mouse functions interacts with with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein forms a ternary membrane complex with DKK1 and the WNT receptor lipoprotein receptor-related protein 6 (LRP6), and induces rapid endocytosis and removal of LRP6 from the plasma membrane. It contains extracellular kringle, WSC, and CUB domains. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.92

Clinical Summary— KREMEN2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

64 VUS of 74 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.83

OE 0.54 (0.33–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.51Z-score

OE missense 0.73 (0.64–0.82)

178 obs / 244.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.33–0.92)

0≤0.351.4

Missense OE?0.73 (0.64–0.82)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 10 / 18.5Missense obs/exp: 178 / 244.5Syn Z: -0.56

This gene — mechanism propensity

0.5968th %ile

GOF

0.6931th %ile

LOF

0.3258th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

74 submitted variants in ClinVar

ClinVar

Classification Summary

VUS64

Likely Benign4

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	64	0	64
Likely Benign	3	1	4
Benign	1	0	1
Total	68	1	69

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

35 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap KREMEN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →