rs202109231

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_004086.3(COCH):c.629+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,607,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

COCH
NM_004086.3 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.0003074

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.248

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 -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 14-30880739-C-T is Benign according to our data. Variant chr14-30880739-C-T is described in ClinVar as [Benign]. Clinvar id is 281981.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-30880739-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00113 (172/151892) while in subpopulation AMR AF= 0.0023 (35/15226). AF 95% confidence interval is 0.0017. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3 linkuse as main transcript	c.629+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000396618.9
LOC100506071	NR_038356.1 linkuse as main transcript	n.1617+3771G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9 linkuse as main transcript	c.629+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_004086.3	P1	O43405-1
	ENST00000555108.1 linkuse as main transcript	n.1617+3771G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

151774

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00105

AC XY:

142

AN XY:

135670

show subpopulations

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.:

Cov.:

AF XY:

0.00110

AC XY:

794

AN XY:

724544

show subpopulations

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.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74190

show subpopulations

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.:

Bravo

AF:

0.00117

EpiCase

AF:

0.00169

EpiControl

AF:

0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	COCH: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 30, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2015	- -

COCH-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2019

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

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Feb 25, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

BayesDel_noAF

Benign

-0.68

Cadd

Benign

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

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