14-30877360-G-C

Position:

• chr14-30877360-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004086.3(COCH):​c.83-212G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 586,844 control chromosomes in the GnomAD database, including 124,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29707 hom., cov: 31)
  • Exomes 𝑓: 0.66 (94728 hom.)
• Consequence: COCH NM_004086.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.499

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-30877360-G-C is Benign according to our data. Variant chr14-30877360-G-C is described in ClinVar as [Benign]. Clinvar id is 1251904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.83-212G>C		intron_variant		ENST00000396618.9
LOC100506071	NR_038356.1	n.1618-808C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.83-212G>C		intron_variant		1	NM_004086.3	P1
	ENST00000555108.1	n.1618-808C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94206 AN: 151834 Hom.: 29691 Cov.: 31

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.809

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.657

GnomAD4 exome AF: 0.656 AC: 285389 AN: 434892 Hom.: 94728 Cov.: 5 AF XY: 0.664 AC XY: 151506 AN XY: 228210

Gnomad4 AFR exome AF: 0.525

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.669

Gnomad4 EAS exome AF: 0.651

Gnomad4 SAS exome AF: 0.800

Gnomad4 FIN exome AF: 0.593

Gnomad4 NFE exome AF: 0.639

Gnomad4 OTH exome AF: 0.654

GnomAD4 genome AF: 0.620 AC: 94264 AN: 151952 Hom.: 29707 Cov.: 31 AF XY: 0.624 AC XY: 46317 AN XY: 74250

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.741

Gnomad4 ASJ AF: 0.659

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.810

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.656

Alfa AF: 0.617 Hom.: 3609

Bravo AF: 0.625

Asia WGS AF: 0.754 AC: 2622 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.6
DANN	Benign	0.35

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: rs1124181; hg19: chr14-31346566;