CNTN5

Chr 11

contactin 5

Also known as: HNB-2s, NB-2

NCBI Gene: 53942 ENSG00000149972 UniProt: O94779 OMIM: 607219

This protein is a GPI-anchored cell adhesion molecule that mediates cell surface interactions and axon connections during nervous system development, with particular involvement in auditory system function. CNTN5 is highly constrained against loss-of-function variants (pLI near 1, LOEUF 0.485), indicating that mutations are likely to cause significant developmental effects. Pathogenic variants cause autosomal recessive intellectual disability with language impairment and autistic features.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the immunoglobulin superfamily, and contactin family, which mediate cell surface interactions during nervous system development. This protein is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.48

Clinical Summary— CNTN5

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

171 VUS of 239 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.000

Z-score 4.62

OE 0.33 (0.23–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.34Z-score

OE missense 1.04 (0.97–1.11)

599 obs / 576.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.33 (0.23–0.48)

0≤0.351.4

Missense OE?1.04 (0.97–1.11)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 18 / 55.0Missense obs/exp: 599 / 576.3Syn Z: -1.77

This gene — mechanism propensity

0.75top 25%

GOF

0.6541th %ile

LOF

0.3550th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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

239 submitted variants in ClinVar

ClinVar

Classification Summary

VUS171

Likely Benign18

Benign13

Conflicting2

171

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	169	1	0	171
Likely Benign	0	7	3	8	18
Benign	0	7	1	5	13
Conflicting	—				2
Total	1	183	5	13	204

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap CNTN5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →