rs17304212

Variant names:

• chr2-178461008-C-G
• rs17304212
• NM_001042702.5:c.793C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178461008-C-G
• chr2-178461008-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001042702.5(PJVK):​c.793C>G​(p.Arg265Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,613,372 control chromosomes in the GnomAD database, including 3,702 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R265C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (270 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3432 hom.)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.20
• Publications: 22 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028193295).
• BP6: Variant 2-178461008-C-G is Benign according to our data. Variant chr2-178461008-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43870.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0666 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PJVK	NM_001042702.5	MANE Select	c.793C>G	p.Arg265Gly	missense	Exon 7 of 7	NP_001036167.1	Q0ZLH3
	PJVK	NM_001353775.2		c.802C>G	p.Arg268Gly	missense	Exon 7 of 7	NP_001340704.1
	PJVK	NM_001353776.2		c.799C>G	p.Arg267Gly	missense	Exon 6 of 6	NP_001340705.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PJVK	ENST00000644580.2	MANE Select	c.793C>G	p.Arg265Gly	missense	Exon 7 of 7	ENSP00000495855.2	Q0ZLH3
	PJVK	ENST00000375129.8	TSL:1	c.793C>G	p.Arg265Gly	missense	Exon 6 of 6	ENSP00000364271.4	Q0ZLH3
	PJVK	ENST00000437056.5	TSL:1	n.1663C>G		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.0558 AC: 8479 AN: 152042 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0558 AC: 13912 AN: 249418 AF XY: 0.0580

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.00484

Gnomad FIN exome AF: 0.0824

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.0639

GnomAD4 exome AF: 0.0653 AC: 95399 AN: 1461212 Hom.: 3432 Cov.: 33 AF XY: 0.0653 AC XY: 47476 AN XY: 726930

African (AFR) AF: 0.0385 AC: 1290 AN: 33474

American (AMR) AF: 0.0339 AC: 1514 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0512 AC: 1338 AN: 26130

East Asian (EAS) AF: 0.00821 AC: 326 AN: 39684

South Asian (SAS) AF: 0.0565 AC: 4866 AN: 86198

European-Finnish (FIN) AF: 0.0791 AC: 4214 AN: 53274

Middle Eastern (MID) AF: 0.0626 AC: 361 AN: 5764

European-Non Finnish (NFE) AF: 0.0700 AC: 77783 AN: 1111582

Other (OTH) AF: 0.0614 AC: 3707 AN: 60384

GnomAD4 genome AF: 0.0558 AC: 8486 AN: 152160 Hom.: 270 Cov.: 32 AF XY: 0.0559 AC XY: 4160 AN XY: 74376

African (AFR) AF: 0.0400 AC: 1659 AN: 41524

American (AMR) AF: 0.0433 AC: 662 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3472

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5190

South Asian (SAS) AF: 0.0542 AC: 262 AN: 4830

European-Finnish (FIN) AF: 0.0865 AC: 912 AN: 10548

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0682 AC: 4637 AN: 67988

Other (OTH) AF: 0.0610 AC: 129 AN: 2114

Alfa AF: 0.00491 Hom.: 497

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0641 AC: 247

ExAC AF: 0.0553 AC: 6682

EpiCase AF: 0.0690

EpiControl AF: 0.0684

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	Autosomal recessive nonsyndromic hearing loss 59 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.18
Sift	Benign	0.035	D
Sift4G	Benign	0.21	T
Polyphen		0.27	B
Vest4		0.20
MPC		0.21
ClinPred		0.010	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.41
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17304212; hg19: chr2-179325735; COSMIC: COSV51846203; COSMIC: COSV51846203;