14-30880739-C-T

Variant names:

• chr14-30880739-C-T
• rs202109231
• NM_004086.3:c.629+5C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.629+5C>T variant in the COCH gene is 0.1% for European chromosomes by gnomAD (162/126474 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7143097/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: COCH NM_004086.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003074
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.248

Genes affected

COCH (HGNC:2180): (cochlin) The protein encoded by this gene is highly conserved in human, mouse, and chicken, showing 94% and 79% amino acid identity of human to mouse and chicken sequences, respectively. Hybridization to this gene was detected in spindle-shaped cells located along nerve fibers between the auditory ganglion and sensory epithelium. These cells accompany neurites at the habenula perforata, the opening through which neurites extend to innervate hair cells. This and the pattern of expression of this gene in chicken inner ear paralleled the histologic findings of acidophilic deposits, consistent with mucopolysaccharide ground substance, in temporal bones from DFNA9 (autosomal dominant nonsyndromic sensorineural deafness 9) patients. Mutations that cause DFNA9 have been reported in this gene. Alternative splicing results in multiple transcript variants encoding the same protein. Additional splice variants encoding distinct isoforms have been described but their biological validities have not been demonstrated. [provided by RefSeq, Oct 2008]

ENSG00000258525 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COCH	NM_004086.3	c.629+5C>T		splice_region_variant, intron_variant	Intron 8 of 11	ENST00000396618.9	NP_004077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9	c.629+5C>T		splice_region_variant, intron_variant	Intron 8 of 11	1	NM_004086.3	ENSP00000379862.3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 151774 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000914 AC: 229 AN: 250524 Hom.: 0 AF XY: 0.00105 AC XY: 142 AN XY: 135670

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.00105 AC: 1529 AN: 1455694 Hom.: 1 Cov.: 29 AF XY: 0.00110 AC XY: 794 AN XY: 724544

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00215

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000906

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00113 AC: 172 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74190

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00230

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00117

EpiCase AF: 0.00169

EpiControl AF: 0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COCH: BP4, BS1 -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jul 30, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.629+5C>T variant in COCH is classified as benign because it has been ident ified in 0.13% (162/126474) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org). In addition, this variant is located in the 5' splice region, and computational tools do not suggest an impact to splicing. ACMG/AMP Criteria applied: BA1, BP4. -

COCH-related disorder Benign:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nonsyndromic genetic hearing loss Benign:1

Feb 25, 2019

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.629+5C>T variant in the COCH gene is 0.1% for European chromosomes by gnomAD (162/126474 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). -

Autosomal dominant nonsyndromic hearing loss 9 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202109231; hg19: chr14-31349945;