Genetic Variant NM_001042702.5:c.195C>G (chr2-178453604-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001042702.5(PJVK):c.195C>G(p.Asp65Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D65N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PJVK
NM_001042702.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.390

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2046006).

BP6

Variant 2-178453604-C-G is Benign according to our data. Variant chr2-178453604-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 179555.Status of the report is criteria_provided_single_submitter, 1 stars.

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.195C>G	p.Asp65Glu	missense	Exon 2 of 7	NP_001036167.1	Q0ZLH3
PJVK	NM_001353775.2		c.204C>G	p.Asp68Glu	missense	Exon 2 of 7	NP_001340704.1
PJVK	NM_001353776.2		c.300C>G	p.Asp100Glu	missense	Exon 2 of 6	NP_001340705.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PJVK	ENST00000644580.2	MANE Select	c.195C>G	p.Asp65Glu	missense	Exon 2 of 7	ENSP00000495855.2	Q0ZLH3
PJVK	ENST00000375129.8	TSL:1	c.195C>G	p.Asp65Glu	missense	Exon 1 of 6	ENSP00000364271.4	Q0ZLH3
PJVK	ENST00000437056.5	TSL:1	n.354C>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460468

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111216

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.087

Eigen

Benign

0.017

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.76

M_CAP

Benign

0.0030

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.17

PhyloP100

0.39

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.2

REVEL

Benign

0.059

Sift

Benign

0.31

Sift4G

Benign

1.0

Polyphen

0.0070

Vest4

0.10

MutPred

0.39

Gain of solvent accessibility (P = 0.0503)

MVP

0.048

MPC

0.099

ClinPred

0.26

GERP RS

4.3

PromoterAI

0.0086

Neutral

(source)

Varity_R

0.087

gMVP

0.21

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over