rs17097468

chr14-30889691-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004086.3(COCH):c.1553A>G(p.Glu518Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,613,950 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E518E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.93

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071074963).
• BP6: Variant 14-30889691-A-G is Benign according to our data. Variant chr14-30889691-A-G is described in ClinVar as [Benign]. Clinvar id is 162972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00565 (861/152280) while in subpopulation AFR AF= 0.0191 (793/41550). AF 95% confidence interval is 0.018. There are 13 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.1553A>G	p.Glu518Gly	missense_variant	12/12	ENST00000396618.9
LOC100506071	NR_038356.1	n.118T>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.1553A>G	p.Glu518Gly	missense_variant	12/12	1	NM_004086.3	P1
	ENST00000555108.1	n.118T>C		non_coding_transcript_exon_variant	1/5	1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152162 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 251326 Hom.: 3 AF XY: 0.00123 AC XY: 167 AN XY: 135838

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000641 AC: 937 AN: 1461670 Hom.: 12 Cov.: 31 AF XY: 0.000573 AC XY: 417 AN XY: 727146

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00565 AC: 861 AN: 152280 Hom.: 13 Cov.: 33 AF XY: 0.00553 AC XY: 412 AN XY: 74464

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.00650

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00196 AC: 238

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Glu518Gly in Exon 12 of COCH: This variant is not expected to have clinical sign ificance because it has been identified in 2.0% (75/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs17097468). -

Autosomal dominant nonsyndromic hearing loss 9 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;.;.;D;D
MetaRNN	Benign	0.0071	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.48	T
REVEL	Uncertain	0.52
Polyphen		0.82	.;P;P;.;P
Vest4		0.35, 0.39
MVP		0.91
MPC		0.41
ClinPred		0.024	T
GERP RS		5.2
Varity_R		0.22
gMVP		0.65

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

Other links and lift over

dbSNP: rs17097468; hg19: chr14-31358897;