chr2-178461008-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001042702.5(PJVK):c.793C>T(p.Arg265Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,613,510 control chromosomes in the GnomAD database, including 4,575 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.054 ( 314 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4261 hom. )

Consequence

PJVK
NM_001042702.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.20

Publications

22 publications found

Variant links:

Genes affected

PJVK (HGNC:29502): (pejvakin) The protein encoded by this gene is a member of the gasdermin family, a family which is found only in vertebrates. The encoded protein is required for the proper function of auditory pathway neurons. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal recessive type 59 (DFNB59). [provided by RefSeq, Dec 2008]

PJVK Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 59
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PJVK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028128922).

BP6

Variant 2-178461008-C-T is Benign according to our data. Variant chr2-178461008-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43871.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042702.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PJVK	NM_001042702.5	MANE Select	c.793C>T	p.Arg265Cys	missense	Exon 7 of 7	NP_001036167.1	Q0ZLH3
PJVK	NM_001353775.2		c.802C>T	p.Arg268Cys	missense	Exon 7 of 7	NP_001340704.1
PJVK	NM_001353776.2		c.799C>T	p.Arg267Cys	missense	Exon 6 of 6	NP_001340705.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PJVK	ENST00000644580.2	MANE Select	c.793C>T	p.Arg265Cys	missense	Exon 7 of 7	ENSP00000495855.2	Q0ZLH3
PJVK	ENST00000375129.8	TSL:1	c.793C>T	p.Arg265Cys	missense	Exon 6 of 6	ENSP00000364271.4	Q0ZLH3
PJVK	ENST00000437056.5	TSL:1	n.1663C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.0545

AC:

8290

AN:

152044

Hom.:

314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0525

Gnomad ASJ

AF:

0.0522

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0745

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0833

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0561

AC:

13990

AN:

249418

AF XY:

0.0562

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.0540

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0734

Gnomad NFE exome

AF:

0.0816

Gnomad OTH exome

AF:

0.0634

GnomAD4 exome

AF:

0.0713

AC:

104255

AN:

1461348

Hom.:

4261

Cov.:

AF XY:

0.0703

AC XY:

51081

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.0106

AC:

354

AN:

33476

American (AMR)

AF:

0.0417

AC:

1866

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0512

AC:

1337

AN:

26130

East Asian (EAS)

AF:

0.000126

AC:

AN:

39684

South Asian (SAS)

AF:

0.0233

AC:

2008

AN:

86208

European-Finnish (FIN)

AF:

0.0739

AC:

3935

AN:

53280

Middle Eastern (MID)

AF:

0.0531

AC:

306

AN:

5766

European-Non Finnish (NFE)

AF:

0.0815

AC:

90634

AN:

1111690

Other (OTH)

AF:

0.0631

AC:

3810

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4792

9584

14377

19169

23961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3174

6348

9522

12696

15870

<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:

0.0545

AC:

8286

AN:

152162

Hom.:

314

Cov.:

AF XY:

0.0534

AC XY:

3969

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0143

AC:

592

AN:

41530

American (AMR)

AF:

0.0524

AC:

801

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0522

AC:

181

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.0205

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0745

AC:

786

AN:

10552

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0833

AC:

5661

AN:

67988

Other (OTH)

AF:

0.0501

AC:

106

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

403

806

1210

1613

2016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0692

Hom.:

497

TwinsUK

AF:

0.0785

AC:

291

ALSPAC

AF:

0.0654

AC:

252

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0837

AC:

687

ExAC

AF:

0.0580

AC:

7001

EpiCase

AF:

0.0829

EpiControl

AF:

0.0779

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Autosomal recessive nonsyndromic hearing loss 59 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

2.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.67

REVEL

Benign

0.23

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.052

Polyphen

0.99

Vest4

0.22

MPC

0.50

ClinPred

0.015

GERP RS

6.0

Varity_R

0.11

gMVP

0.44

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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