CEACAM16

protein-coding

CEA cell adhesion molecule 16, tectorial membrane component, the group of CEA cell adhesion molecule family|V-set domain containing

Gene summary

The protein encoded by this gene is a secreted glycoprotein that in mouse interacts with tectorial membrane proteins in the inner ear. The encoded adhesion protein is found in cochlear outer hair cells and appears to be important for proper hearing over an extended frequency range. Defects in this gene likely are a cause of non-syndromic autosomal dominant hearing loss. [provided by RefSeq, May 2012]

MANE transcript

NM_001039213.4

Inheritance

AR, AD

ClinVar variants

P:22U:173B:91

Top phenotype

Deafness, autosomal dominant 4B; Deafness, autosomal recessive 113

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr19:44,699,151-44,710,718

External References & Databases

Ensembl (ENSG00000213892)

Transcript & Mutation Effects

hg38 • Region Span ~11.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

CEACAM16 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2018 (Booth et al., PMID: 29703829). The split curation for autosomal dominant nonsyndromic hearing loss is curated separately. The mechanism of pathogenicity is reported to be loss of function (PMID: 29703829). Four variants (missense, splicing, nonsense) that have been reported in four homozygous probands in three publications (PMIDs: 29703829, 30514912, 33111345) are included in this curation. Variants in this gene segregated with disease in 8 additional family members. This gene-disease relationship is also supported by two mouse models, expression data, and protein interaction data (PMIDs: 31249509, 25080593, 21368133, 22544735). In summary, there is strong evidence to support the relationship between CEACAM16 and autosomal recessive nonsyndromic hearing loss. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 12.21.2022 (SOP Version 9).

autosomal dominant nonsyndromic hearing loss 4BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013823

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessive 113STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032732

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

CEACAM16 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2011 (Zheng et al., PMID: 21368133). The split curation for autosomal recessive hearing loss will be curated separately. Five variants (missense, frameshift) that have been reported in five probands in five publications (PMIDs: 21368133, 25589040, 26648831, 28000701, 35292975) are included in this curation. The mechanism of pathogenicity is unknown. This gene-disease relationship is also supported by mouse models and expression data (PMIDs:22544735, 21368133). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 03/20/2018. It was reevaluated on 09/21/2022. A new case with hearing loss (35292975) was scored, but two new mouse model studies were not, due to inconsistent inheritance pattern (PMIDs: 25080593, 31249509) and the classification did not change (SOP Version 9).

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 4B; Deafness, autosomal recessive 113AD/AR

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7655461; 21368133; 29703829

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEACAM16 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 224

Inborn genetic diseasesTotal: 85

not specifiedTotal: 60

CEACAM16-related disorderTotal: 43

Autosomal dominant nonsyndromic hearing loss 4BTotal: 16

Hearing loss, autosomal recessive 113Total: 10

Nonsyndromic genetic hearing lossTotal: 3

Hearing impairmentTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039213.4. 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			6 clinvar	57 clinvar	3 clinvar	66
missense	2 clinvar	8 clinvar	164 clinvar	30 clinvar	1 clinvar	205
nonsense	3 clinvar	4 clinvar	1 clinvar			8
start loss						0
frameshift	2 clinvar	2 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	8	14	173	87	4	286

Highest pathogenic variant AF is 0.000055882294

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039213.4	RefSeq	NP_001034302.2	6	MANE Select
ENST00000587331.7	Ensembl	ENSP00000466561.1	6	MANE Select
ENST00000405314.2	Ensembl	ENSP00000385576.1	6	Standard
ENST00000405314.3	Ensembl	ENSP00000385576.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound

Molecular Function

identical protein binding

Cellular Component

extracellular space
stereocilium tip

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000587331
Coding exons: 6
Length: 11566
Individuals with no LoFs: 124631
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 124656
p: 0.000100

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.524	253	278	0.911	0.0000193	2665
Missense (PolyPhen)		134	148.66	0.90141		1430
Synonymous	0.0403	129	130	0.995	0.00000950	933
Loss of Function	1.47	10	16.4	0.609	8.49e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00028	0.00026	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0	0.0	absent
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for proper hearing, it may play a role in maintaining the integrity of the tectorial membrane. {ECO:0000269|PubMed:21368133, ECO:0000269|PubMed:25589040}.;
Disease: DISEASE: Deafness, autosomal dominant, 4B (DFNA4B) [MIM:614614]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:21368133, ECO:0000269|PubMed:25589040}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.498
RVIS EVS: -0.4
RVIS percentile EVS: 26.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

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