14-30878831-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5

The NM_004086.3(COCH):​c.260G>T​(p.Gly87Val) 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 Lovd as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. 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

Scores

14
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.13
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS1
Transcript NM_004086.3 (COCH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 14-30878831-G-T is Pathogenic according to our data. Variant chr14-30878831-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COCHNM_004086.3 linkc.260G>T p.Gly87Val missense_variant Exon 5 of 12 ENST00000396618.9 NP_004077.1 O43405-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COCHENST00000396618.9 linkc.260G>T p.Gly87Val missense_variant Exon 5 of 12 1 NM_004086.3 ENSP00000379862.3 O43405-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
.;D;D;.;.;.;D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;.;.;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
4.0
.;H;H;.;H;.;H
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-5.3
.;D;.;.;D;D;.
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
.;D;.;.;D;D;.
Sift4G
Pathogenic
0.0
.;D;.;.;D;D;.
Polyphen
1.0
.;D;D;.;.;.;D
Vest4
0.90, 0.94
MutPred
0.95
.;Loss of glycosylation at S86 (P = 0.0246);Loss of glycosylation at S86 (P = 0.0246);Loss of glycosylation at S86 (P = 0.0246);Loss of glycosylation at S86 (P = 0.0246);.;Loss of glycosylation at S86 (P = 0.0246);
MVP
0.99
MPC
0.91
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.91

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555310861; hg19: chr14-31348037; API