chr14-30875299-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_StrongBS1_Supporting

The NM_001347720.2(COCH):c.277+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 810,588 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

COCH
NM_001347720.2 splice_donor, intron

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.208

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: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13149351 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000729 (48/658332) while in subpopulation EAS AF = 0.000371 (12/32318). AF 95% confidence interval is 0.000214. There are 1 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 8. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	Effect	Exon Rank	Protein	UniProt
COCH	NM_004086.3	MANE Select	c.82+196G>A	intron	N/A	NP_004077.1	O43405-1
COCH	NM_001347720.2		c.277+1G>A	splice_donor intron	N/A	NP_001334649.1	A0A2U3TZE7
COCH	NM_001135058.2		c.82+196G>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.82+196G>A	intron	N/A	ENSP00000379862.3	O43405-1
COCH	ENST00000216361.9	TSL:1	c.277+1G>A	splice_donor intron	N/A	ENSP00000216361.5	A0A2U3TZE7
COCH	ENST00000475087.5	TSL:1	c.82+196G>A	intron	N/A	ENSP00000451528.1	O43405-2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD4 exome

AF:

0.0000729

AC:

AN:

658332

Hom.:

Cov.:

AF XY:

0.0000738

AC XY:

AN XY:

338844

show subpopulations

African (AFR)

AF:

0.000183

AC:

AN:

16394

American (AMR)

AF:

0.00

AC:

AN:

20512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15232

East Asian (EAS)

AF:

0.000371

AC:

AN:

32318

South Asian (SAS)

AF:

0.00

AC:

AN:

51254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2396

European-Non Finnish (NFE)

AF:

0.00000219

AC:

AN:

457288

Other (OTH)

AF:

0.000969

AC:

AN:

33014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.0000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41466

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000577

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000142

Hom.:

Bravo

AF:

0.000125

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

COCH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.3

(source)

DANN

Benign

0.75

FATHMM_MKL

Benign

0.13

PhyloP100

0.21

GERP RS

-0.82

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 4

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