rs1555310861

Positions:

• chr14-30878831-G-C
• chr14-30878831-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004086.3(COCH):​c.260G>C​(p.Gly87Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G87W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.13

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain LCCL (size 93) in uniprot entity COCH_HUMAN there are 30 pathogenic changes around while only 6 benign (83%) in NM_004086.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-30878830-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1297642.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 14-30878831-G-C is Pathogenic according to our data. Variant chr14-30878831-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517362.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.260G>C	p.Gly87Ala	missense_variant	5/12	ENST00000396618.9
LOC100506071	NR_038356.1	n.1618-2279C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.260G>C	p.Gly87Ala	missense_variant	5/12	1	NM_004086.3	P1
	ENST00000555108.1	n.1618-2279C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 13, 2019

The p.Gly87Ala variant in COCH has been reported in one individual with adult-onset autosomal dominant hearing loss and segregated in two affected relatives. It has not been identified in large population studies. Glycine (Gly) at position 87 is highly conserved in mammals and evolutionarily distant species, raising the possibility that a change at this position may not be tolerated. Furthermore, two different variants at the same amino acid position (p.Gly87Val and p.Gly87Trp) have been previously reported to segregate with hearing loss in 3 families manifesting autosomal dominant sensorineural hearing loss and vestibular dysfunction (Chen 2013, Collin 2006, Yang 2013). It is located in a functional domain enriched with variants identified in hearing loss patients (Bae 2014). In summary, while additional studies are required to establish fully its clinical significance, the p.Gly87Ala variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP4, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;D;.;.;.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;.;.;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.2	.;M;M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.7	.;D;.;.;D;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;D;.;.;D;D;.
Sift4G	Pathogenic	0.0	.;D;.;.;D;D;.
Polyphen		1.0	.;D;D;.;.;.;D
Vest4		0.71, 0.67
MutPred		0.94		.;Loss of glycosylation at S86 (P = 0.0426);Loss of glycosylation at S86 (P = 0.0426);Loss of glycosylation at S86 (P = 0.0426);Loss of glycosylation at S86 (P = 0.0426);.;Loss of glycosylation at S86 (P = 0.0426);
MVP		0.97
MPC		0.84
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.84

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: rs1555310861; hg19: chr14-31348037;