14-30875307-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004086.3(COCH):c.82+204C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 721,896 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (49 hom.)
• Consequence: COCH NM_004086.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.372

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=-0.78).
• BP6: Variant 14-30875307-C-G is Benign according to our data. Variant chr14-30875307-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1190096.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00575 (876/152346) while in subpopulation AMR AF= 0.0397 (608/15308). AF 95% confidence interval is 0.0371. There are 21 homozygotes in gnomad4. There are 552 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.82+204C>G		intron_variant		ENST00000396618.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.82+204C>G		intron_variant		1	NM_004086.3	P1

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 879 AN: 152228 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00311 AC: 1769 AN: 569550 Hom.: 49 Cov.: 7 AF XY: 0.00284 AC XY: 843 AN XY: 296722

Gnomad4 AFR exome AF: 0.000275

Gnomad4 AMR exome AF: 0.0500

Gnomad4 ASJ exome AF: 0.000137

Gnomad4 EAS exome AF: 0.0000626

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.00509

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152346 Hom.: 21 Cov.: 32 AF XY: 0.00741 AC XY: 552 AN XY: 74496

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.0397

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00658

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.86
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7158281; hg19: chr14-31344513;