14-30877274-G-A

Position:

• chr14-30877274-G-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.83-298G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 373,848 control chromosomes in the GnomAD database, including 559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (165 hom., cov: 32)
  • Exomes 𝑓: 0.054 (394 hom.)
• Consequence: COCH NM_004086.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.62

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=-1.03).
• BP6: Variant 14-30877274-G-A is Benign according to our data. Variant chr14-30877274-G-A is described in ClinVar as [Benign]. Clinvar id is 1221585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COCH	NM_004086.3	c.83-298G>A		intron_variant		ENST00000396618.9	NP_004077.1
LOC100506071	NR_038356.1	n.1618-722C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COCH	ENST00000396618.9	c.83-298G>A		intron_variant		1	NM_004086.3	ENSP00000379862	P1
	ENST00000555108.1	n.1618-722C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5822 AN: 152042 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.00998

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0674

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0597

Gnomad OTH AF: 0.0379

GnomAD4 exome AF: 0.0536 AC: 11877 AN: 221690 Hom.: 394 AF XY: 0.0557 AC XY: 6644 AN XY: 119340

Gnomad4 AFR exome AF: 0.00964

Gnomad4 AMR exome AF: 0.0253

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.0000932

Gnomad4 SAS exome AF: 0.0716

Gnomad4 FIN exome AF: 0.0295

Gnomad4 NFE exome AF: 0.0601

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0382 AC: 5820 AN: 152158 Hom.: 165 Cov.: 32 AF XY: 0.0372 AC XY: 2768 AN XY: 74390

Gnomad4 AFR AF: 0.00995

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0476

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0677

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0597

Gnomad4 OTH AF: 0.0375

Alfa AF: 0.0209 Hom.: 14

Bravo AF: 0.0369

Asia WGS AF: 0.0210 AC: 74 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	Dec 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.74

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: rs77298564; hg19: chr14-31346480;