rs727504604

chr2-178460363-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042702.5(PJVK):c.683C>T(p.Ser228Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S228S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28022194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJVK	NM_001042702.5	c.683C>T	p.Ser228Leu	missense_variant	6/7	ENST00000644580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2	c.683C>T	p.Ser228Leu	missense_variant	6/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 31, 2013

The Ser228Leu variant in DFNB59 has not been previously reported in individuals with hearing loss or observed in large population studies. Computational analys es (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and S IFT) do not provide strong support for or against an impact to the protein. In s ummary, additional data is needed to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.67	T
Polyphen		0.0060	.;B;.;B;.;.;B;.
Vest4		0.37
MutPred		0.50		.;Loss of disorder (P = 0.0165);.;Loss of disorder (P = 0.0165);.;.;Loss of disorder (P = 0.0165);.;
MVP		0.22
MPC		0.11
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.20
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504604; hg19: chr2-179325090;