14-30890641-T-A

Position:

• chr14-30890641-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000475087.5(COCH):​c.1478-4272T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 903,162 control chromosomes in the GnomAD database, including 210,050 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39359 hom., cov: 33)
  • Exomes 𝑓: 0.67 (170691 hom.)
• Consequence: COCH ENST00000475087.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COCH	NM_004086.3			downstream_gene_variant		ENST00000396618.9	NP_004077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9			downstream_gene_variant		1	NM_004086.3	ENSP00000379862	P1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108770 AN: 152030 Hom.: 39308 Cov.: 33

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.703

GnomAD4 exome AF: 0.672 AC: 504753 AN: 751014 Hom.: 170691 Cov.: 11 AF XY: 0.672 AC XY: 234530 AN XY: 349036

Gnomad4 AFR exome AF: 0.772

Gnomad4 AMR exome AF: 0.788

Gnomad4 ASJ exome AF: 0.699

Gnomad4 EAS exome AF: 0.974

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.648

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.691

GnomAD4 genome AF: 0.716 AC: 108883 AN: 152148 Hom.: 39359 Cov.: 33 AF XY: 0.718 AC XY: 53420 AN XY: 74372

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.772

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.978

Gnomad4 SAS AF: 0.713

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.706

Alfa AF: 0.671 Hom.: 4076

Bravo AF: 0.731

Asia WGS AF: 0.843 AC: 2931 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.34
DANN	Benign	0.51

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6571366; hg19: chr14-31359847;