14-30878920-T-C

Position:

• chr14-30878920-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004086.3(COCH):​c.349T>C​(p.Trp117Arg) variant causes a missense change. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.54

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 10 ACMG points.

• PM1: In a domain LCCL (size 93) in uniprot entity COCH_HUMAN there are 22 pathogenic changes around while only 3 benign (88%) in NM_004086.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 14-30878920-T-C is Pathogenic according to our data. Variant chr14-30878920-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6610.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-30878920-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COCH	NM_004086.3	c.349T>C	p.Trp117Arg	missense_variant	5/12	ENST00000396618.9	NP_004077.1
LOC100506071	NR_038356.1	n.1618-2368A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9	c.349T>C	p.Trp117Arg	missense_variant	5/12	1	NM_004086.3	ENSP00000379862	P1
	ENST00000555108.1	n.1618-2368A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1998

- -

Hereditary hearing loss and deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 09, 2024

Variant summary: COCH c.349T>C (p.Trp117Arg) results in a non-conservative amino acid change located in the LCCL domain (IPR004043) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.349T>C has been reported in the literature in multiple individuals frome a family affected with Hereditary hearing loss and deafness (example, Baek_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 50% of normal Cochlin cleavage ability (Jung_2015). The following publications have been ascertained in the context of this evaluation (PMID: 20447147, 26256111). ClinVar contains an entry for this variant (Variation ID: 6610). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;D;D;.;.;.;T;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;.;.;T;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.5	.;M;M;.;M;.;.;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.9	.;D;.;.;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	.;D;.;.;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;.;.;D;D;D;.
Polyphen		1.0	.;D;D;.;.;.;.;D
Vest4		0.86, 0.84, 0.90
MutPred		0.82		.;Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);.;.;Gain of disorder (P = 0.005);
MVP		0.99
MPC		0.95
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs121908929; hg19: chr14-31348126;