dbSNP rs149627009: COCH:p.Ala77Ala (chr14-30875252-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS1

The NM_001347720.2(COCH):c.231G>A(p.Ala77Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,115,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

COCH
NM_001347720.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -2.14

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 14-30875252-G-A is Benign according to our data. Variant chr14-30875252-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3053770.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152326) while in subpopulation SAS AF = 0.000414 (2/4834). AF 95% confidence interval is 0.000292. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347720.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COCH	NM_004086.3	MANE Select	c.82+149G>A		intron	N/A	NP_004077.1	O43405-1
COCH	NM_001347720.2		c.231G>A	p.Ala77Ala	synonymous	Exon 2 of 11	NP_001334649.1	A0A2U3TZE7
COCH	NM_001135058.2		c.82+149G>A		intron	N/A	NP_001128530.1	O43405-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COCH	ENST00000216361.9	TSL:1	c.231G>A	p.Ala77Ala	synonymous	Exon 2 of 11	ENSP00000216361.5	A0A2U3TZE7
COCH	ENST00000396618.9	TSL:1 MANE Select	c.82+149G>A		intron	N/A	ENSP00000379862.3	O43405-1
COCH	ENST00000475087.5	TSL:1	c.82+149G>A		intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000312

AC:

300

AN:

963014

Hom.:

Cov.:

AF XY:

0.000329

AC XY:

159

AN XY:

483224

show subpopulations

African (AFR)

AF:

0.0000433

AC:

AN:

23112

American (AMR)

AF:

0.00

AC:

AN:

28154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18580

East Asian (EAS)

AF:

0.00

AC:

AN:

33684

South Asian (SAS)

AF:

0.000326

AC:

AN:

61424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3100

European-Non Finnish (NFE)

AF:

0.000373

AC:

269

AN:

720938

Other (OTH)

AF:

0.000231

AC:

AN:

43368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000236

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000185

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

COCH-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.015

(source)

DANN

Benign

0.93

PhyloP100

-2.1

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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