rs727504487

Positions:

• chr2-178461198-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001042702.5(PJVK):​c.983G>A​(p.Cys328Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PJVK	NM_001042702.5	c.983G>A	p.Cys328Tyr	missense_variant	7/7	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2	c.983G>A	p.Cys328Tyr	missense_variant	7/7		NM_001042702.5	ENSP00000495855	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 16, 2013

The Cys328Tyr variant in DFNB59 has not been reported in individuals affected wi th hearing loss or in large population studies. Computational analyses (biochemi cal amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the C ys328Tyr variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, additional data is needed to d etermine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;T;.;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;.;.;.;.;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	.;L;.;L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	.;.;.;D;.;.;.;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	.;.;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;.;D
Polyphen		0.99	.;D;.;D;.;.;.;D
Vest4		0.94, 0.93
MutPred		0.83		.;Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);.;.;.;Gain of sheet (P = 0.0344);
MVP		0.34
MPC		0.68
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs727504487; hg19: chr2-179325925;