CD96

protein-coding

CD96 molecule, the group of Immunoglobulin like domain containing|CD molecules|Ig-like cell adhesion molecule family

Gene summary

The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

MANE transcript

NM_005816.5

Inheritance

AR, AD

ClinVar variants

P:5U:122B:52

Top phenotype

C syndrome

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr3:111,292,719-111,665,996

External References & Databases

Ensembl (ENSG00000153283)

Transcript & Mutation Effects

hg38 • Region Span ~373.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

C syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008893

Submitter: Labcorp Genetics (formerly Invitae)

C syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008893

Submitter: Ambry Genetics

C syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008893

Submitter: G2P

C syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008893

Submitter: ClinGen

*CD96* was first reported in relation to autosomal dominant Opitz C Syndrome in 2007 (Kaname et al., PMID:17847009). At least 1 variant (missense) has been reported in 1 proband (PMID:17847009). A Cd96 -/- mouse model did present any neurodevelopmental phenotype and the mice were mainly, phenotypically normal (PMID: 24658051). Therefore this mouse model was not scored. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal relationship, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on meeting date 01/16/2025 (SOP Version 11)

Clinical Genomic Database (CGD)

C syndromeAD

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Refs: 7258228; 3981579; 2260586; 10405439; 16835930; 16528754; 17847009

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD96 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 154

not providedTotal: 87

C syndromeTotal: 21

CD96-related disorderTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005816.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	27 clinvar	2 clinvar	30
missense	1 clinvar		105 clinvar	19 clinvar	2 clinvar	127
nonsense		1 clinvar	6 clinvar			7
start loss			1 clinvar			1
frameshift		1 clinvar	4 clinvar	1 clinvar		6
splice donor/acceptor (+/-2bp)		2 clinvar	5 clinvar	1 clinvar		8
Total	1	4	122	48	4	179

Highest pathogenic variant AF is 0.000026123107

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005816.5	RefSeq	NP_005807.1	14	MANE Select
ENST00000352690.9	Ensembl	ENSP00000342040.3	14	MANE Select
NM_001318889.2	RefSeq	NP_001305818.1	8	Standard
NM_001410800.1	RefSeq	NP_001397729.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Immune System
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
Adaptive Immune System

Biological Process

cytokine production involved in inflammatory response
negative regulation of natural killer cell cytokine production
immune response
cell adhesion
cell-matrix adhesion

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
adherens junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000283285
Coding exons: 15
Length: 373032
Individuals with no LoFs: 125225
Homozygous LoFs: 6
Heterozygous LoFs: 516
Defined: 125747
p: 0.00208

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.467	329	306	1.08	0.0000149	3837
Missense (PolyPhen)		76	70.09	1.0843		930
Synonymous	-1.21	126	110	1.15	0.00000581	1105
Loss of Function	1.69	22	32.4	0.679	0.00000157	393

Population LoF Frequency

Population	CAF	p-value	Status
African	0.016	0.016	notable
Latino/Admixed American	0.0023	0.0023	notable
Ashkenazi Jewish	0.00099	0.00099	rare
East Asian	0.0064	0.0064	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00042	0.00042	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in adhesive interactions of activated T and NK cells during the late phase of the immune response. Promotes NK cell-target adhesion by interacting with PVR present on target cells. May function at a time after T and NK cells have penetrated the endothelium using integrins and selectins, when they are actively engaging diseased cells and moving within areas of inflammation.;
Disease: DISEASE: C syndrome (CSYN) [MIM:211750]: A syndrome characterized by trigonocephaly, severe mental retardation, hypotonia, variable cardiac defects, redundant skin, and dysmorphic facial features, including upslanted palpebral fissures, epicanthal folds, depressed nasal bridge, and low-set, posteriorly rotated ears. {ECO:0000269|PubMed:17847009}. Note=The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving CD96 has been found in a patient with C syndrome. Translocation t(3;18)(q13.13;q12.1). CD96 gene was located at the 3q13.13 breakpoint. Precise structural analysis around the breakpoint showed that the gene was disrupted by the translocation in exon 5, probably leading to premature termination or loss of expression of CD96 protein. No gene was detected at the chromosome 18 breakpoint.;

Recessive Scores

pRec: 0.0762

Intolerance Scores

LoFtool: 0.980
RVIS EVS: -0.6
RVIS percentile EVS: 18.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0357

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium