14-30875307-C-G

Variant names:

• chr14-30875307-C-G
• rs7158281
• NM_004086.3:c.82+204C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

COCH Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive 110

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004086.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	NM_004086.3	MANE Select	c.82+204C>G		intron	N/A	NP_004077.1	O43405-1
	COCH	NM_001347720.2		c.277+9C>G		intron	N/A	NP_001334649.1	A0A2U3TZE7
	COCH	NM_001135058.2		c.82+204C>G		intron	N/A	NP_001128530.1	O43405-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COCH	ENST00000396618.9	TSL:1 MANE Select	c.82+204C>G		intron	N/A	ENSP00000379862.3	O43405-1
	COCH	ENST00000216361.9	TSL:1	c.277+9C>G		intron	N/A	ENSP00000216361.5	A0A2U3TZE7
	COCH	ENST00000475087.5	TSL:1	c.82+204C>G		intron	N/A	ENSP00000451528.1	O43405-2

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

African (AFR) AF: 0.000275 AC: 4 AN: 14548

American (AMR) AF: 0.0500 AC: 992 AN: 19850

Ashkenazi Jewish (ASJ) AF: 0.000137 AC: 2 AN: 14620

East Asian (EAS) AF: 0.0000626 AC: 2 AN: 31938

South Asian (SAS) AF: 0.000101 AC: 5 AN: 49332

European-Finnish (FIN) AF: 0.0118 AC: 351 AN: 29818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2202

European-Non Finnish (NFE) AF: 0.000689 AC: 260 AN: 377196

Other (OTH) AF: 0.00509 AC: 153 AN: 30046

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

African (AFR) AF: 0.000577 AC: 24 AN: 41590

American (AMR) AF: 0.0397 AC: 608 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0158 AC: 168 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00658

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.86
DANN	Benign	0.41
PhyloP100		-0.37
PromoterAI		0.0033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs7158281; hg19: chr14-31344513;