14-30877304-C-A

Position:

• chr14-30877304-C-A

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.83-268C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 407,546 control chromosomes in the GnomAD database, including 865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (609 hom., cov: 32)
  • Exomes 𝑓: 0.030 (256 hom.)
• Consequence: COCH NM_004086.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.500

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=-0.91).
• BP6: Variant 14-30877304-C-A is Benign according to our data. Variant chr14-30877304-C-A is described in ClinVar as [Benign]. Clinvar id is 1241517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.83-268C>A		intron_variant		ENST00000396618.9
LOC100506071	NR_038356.1	n.1618-752G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.83-268C>A		intron_variant		1	NM_004086.3	P1
	ENST00000555108.1	n.1618-752G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0625 AC: 9455 AN: 151332 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.0309

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0437

GnomAD4 exome AF: 0.0296 AC: 7591 AN: 256096 Hom.: 256 Cov.: 3 AF XY: 0.0293 AC XY: 4027 AN XY: 137444

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0260

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0625 AC: 9465 AN: 151450 Hom.: 609 Cov.: 32 AF XY: 0.0618 AC XY: 4577 AN XY: 74038

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0281

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0986

Gnomad4 SAS AF: 0.0310

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0209

Gnomad4 OTH AF: 0.0446

Alfa AF: 0.0185 Hom.: 19

Bravo AF: 0.0673

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	Dec 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.7
DANN	Benign	0.55

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: rs2284654; hg19: chr14-31346510;