rs61759484

Positions:

chr14-30886105-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004086.3(COCH):c.1270T>G(p.Tyr424Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,120 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y424C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 14 hom. )

Consequence

COCH
NM_004086.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.61

Variant links:

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]

COCH links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017714053).

BP6

Variant 14-30886105-T-G is Benign according to our data. Variant chr14-30886105-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 226527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (362/152344) while in subpopulation NFE AF= 0.00419 (285/68042). AF 95% confidence interval is 0.00379. There are 1 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3 linkuse as main transcript	c.1270T>G	p.Tyr424Asp	missense_variant	11/12	ENST00000396618.9
LOC100506071	NR_038356.1 linkuse as main transcript	n.760A>C		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9 linkuse as main transcript	c.1270T>G	p.Tyr424Asp	missense_variant	11/12	1	NM_004086.3	P1	O43405-1
	ENST00000555108.1 linkuse as main transcript	n.760A>C		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

361

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00419

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00267

AC:

671

AN:

251388

Hom.:

AF XY:

0.00249

AC XY:

338

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00480

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00385

AC:

5627

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

2755

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00204

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.00461

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00238

AC:

362

AN:

152344

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00419

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00357

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00308

AC:

374

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COCH: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	This variant is associated with the following publications: (PMID: 26351166) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Tyr424Asp in Exon 11 of COCH: This variant is not expected to have clinical sign ificance because it has been identified in 0.5% (37/7020) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs61759484). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2020	- -

COCH-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2020

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). -

Autosomal dominant nonsyndromic hearing loss 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;D;D;.;.;T;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;.;.;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.018

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.5

.;M;M;.;M;.;M

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.3

.;D;.;.;D;D;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0020

.;D;.;.;D;D;.

Sift4G

Uncertain

0.021

.;D;.;.;T;D;.

Polyphen

0.96

.;D;D;.;.;.;D

Vest4

0.71, 0.69, 0.66

MVP

0.94

MPC

0.77

ClinPred

0.066

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over