14-30874833-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000216361.9(COCH):c.-106A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,325,606 control chromosomes in the GnomAD database, including 9,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1006 hom., cov: 33)
  • Exomes 𝑓: 0.12 (8418 hom.)
• Consequence: COCH ENST00000216361.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.671

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 14-30874833-A-G is Benign according to our data. Variant chr14-30874833-A-G is described in ClinVar as [Benign]. Clinvar id is 682803.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.-23-83A>G		intron_variant		ENST00000396618.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.-23-83A>G		intron_variant		1	NM_004086.3	P1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17025 AN: 151826 Hom.: 1004 Cov.: 33

Gnomad AFR AF: 0.0943

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.117 AC: 137616 AN: 1173662 Hom.: 8418 Cov.: 17 AF XY: 0.118 AC XY: 70460 AN XY: 596596

Gnomad4 AFR exome AF: 0.0929

Gnomad4 AMR exome AF: 0.0727

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.0803

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.112 AC: 17031 AN: 151944 Hom.: 1006 Cov.: 33 AF XY: 0.112 AC XY: 8302 AN XY: 74290

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.0921

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0937

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.122

Alfa AF: 0.112 Hom.: 918

Bravo AF: 0.112

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.0
Dann	Benign	0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11555426; hg19: chr14-31344039; COSMIC: COSV53550560; COSMIC: COSV53550560;