rs28362775

chr14-30885501-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_004086.3(COCH):c.841G>A(p.Asp281Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 3.09

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009686917).
• BP6: Variant 14-30885501-G-A is Benign according to our data. Variant chr14-30885501-G-A is described in ClinVar as [Benign]. Clinvar id is 226529.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00161 (246/152334) while in subpopulation AFR AF= 0.00585 (243/41574). AF 95% confidence interval is 0.00524. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.841G>A	p.Asp281Asn	missense_variant	10/12	ENST00000396618.9
LOC100506071	NR_038356.1	n.1364C>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.841G>A	p.Asp281Asn	missense_variant	10/12	1	NM_004086.3	P1
	ENST00000555108.1	n.1364C>T		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000445 AC: 112 AN: 251470 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135910

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1461330 Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93 AN XY: 726998

Gnomad4 AFR exome AF: 0.00595

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00161 AC: 246 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00156 AC XY: 116 AN XY: 74508

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.00204

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2017	The c.841G>A; p.Asp281Asn variant (rs28362775) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.6 percent in the African population (identified on 145 out of 24,032 chromosomes), and has been reported to the ClinVar database (Variation ID: 226529). The aspartic acid at position 281 is moderately conserved across 12 species (Alamut v2.9.0) and computational analyses of the effects of the p.Asp281Asn variant on protein structure and function indicate a neutral effect (SIFT: tolerated, Align GVGD: C0, PolyPhen-2: benign). Based on these observations the p.Asp281Asn is likely to be benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Asp281Asn in Exon 10 of COCH: This variant is not expected to have clinical sign ificance because it has been identified in 0.7% (25/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs28362775). -

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.841G>A (p.Asp281Asn) variant in the COCH gene is 0.5% for African chromosomes by gnomAD (145/24032 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 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	0.076
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.082
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;.;.;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0097	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
REVEL	Benign	0.20
Polyphen		0.0010	.;B;B;.;.;.;.;B
Vest4		0.17, 0.18, 0.19
MVP		0.89
MPC		0.26
ClinPred		0.021	T
GERP RS		4.6
Varity_R		0.061
gMVP		0.61

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: rs28362775; hg19: chr14-31354707;