chr14-30886321-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004086.3(COCH):c.1477+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,613,692 control chromosomes in the GnomAD database, including 3,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 302 hom., cov: 33)

Exomes 𝑓: 0.059 ( 3167 hom. )

Consequence

COCH
NM_004086.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.328

Publications

10 publications found

Variant links:

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

COCH links:

ENSG00000258525 (HGNC:58454):

ENSG00000258525 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 14-30886321-C-A is Benign according to our data. Variant chr14-30886321-C-A is described in ClinVar as Benign. ClinVar VariationId is 226528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COCH	NM_004086.3	MANE Select	c.1477+9C>A	intron	N/A	NP_004077.1	O43405-1
COCH	NM_001347720.2		c.1672+9C>A	intron	N/A	NP_001334649.1	A0A2U3TZE7
COCH	NM_001135058.2		c.1477+9C>A	intron	N/A	NP_001128530.1	O43405-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COCH	ENST00000396618.9	TSL:1 MANE Select	c.1477+9C>A	intron	N/A	ENSP00000379862.3	O43405-1
COCH	ENST00000216361.9	TSL:1	c.1672+9C>A	intron	N/A	ENSP00000216361.5	A0A2U3TZE7
COCH	ENST00000475087.5	TSL:1	c.1477+9C>A	intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes

AF:

0.0533

AC:

8112

AN:

152128

Hom.:

301

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0248

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.0840

Gnomad FIN

AF:

0.0710

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0538

Gnomad OTH

AF:

0.0516

GnomAD2 exomes

AF:

0.0667

AC:

16628

AN:

249448

AF XY:

0.0675

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.0655

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.176

Gnomad FIN exome

AF:

0.0647

Gnomad NFE exome

AF:

0.0529

Gnomad OTH exome

AF:

0.0563

GnomAD4 exome

AF:

0.0592

AC:

86463

AN:

1461446

Hom.:

3167

Cov.:

AF XY:

0.0601

AC XY:

43695

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0223

AC:

747

AN:

33474

American (AMR)

AF:

0.0666

AC:

2976

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

760

AN:

26130

East Asian (EAS)

AF:

0.171

AC:

6777

AN:

39700

South Asian (SAS)

AF:

0.0907

AC:

7817

AN:

86176

European-Finnish (FIN)

AF:

0.0655

AC:

3496

AN:

53370

Middle Eastern (MID)

AF:

0.0552

AC:

318

AN:

5766

European-Non Finnish (NFE)

AF:

0.0539

AC:

59932

AN:

1111764

Other (OTH)

AF:

0.0603

AC:

3640

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

3788

7575

11363

15150

18938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2324

4648

6972

9296

11620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0533

AC:

8122

AN:

152246

Hom.:

302

Cov.:

AF XY:

0.0557

AC XY:

4147

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0249

AC:

1033

AN:

41532

American (AMR)

AF:

0.0710

AC:

1086

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

946

AN:

5168

South Asian (SAS)

AF:

0.0840

AC:

405

AN:

4820

European-Finnish (FIN)

AF:

0.0710

AC:

753

AN:

10608

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0537

AC:

3655

AN:

68024

Other (OTH)

AF:

0.0553

AC:

117

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

388

776

1164

1552

1940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0544

Hom.:

517

Bravo

AF:

0.0510

Asia WGS

AF:

0.138

AC:

479

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Autosomal dominant nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.6

(source)

DANN

Benign

0.64

PhyloP100

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over