rs727504604

Variant names:

• chr2-178460363-C-T
• rs727504604
• NM_001042702.5:c.683C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PJVK	NM_001042702.5	c.683C>T	p.Ser228Leu	missense_variant	Exon 6 of 7	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2	c.683C>T	p.Ser228Leu	missense_variant	Exon 6 of 7		NM_001042702.5	ENSP00000495855.2

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

Jul 31, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.23	.;T;.;T;.;.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;.;.;.;.;D;D;D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;.;L;.;.;L;.
PhyloP100		6.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	.;.;.;N;.;.;N;.
REVEL	Benign	0.15
Sift	Benign	0.24	.;.;.;T;.;.;T;.
Sift4G	Uncertain	0.017	.;.;.;D;.;.;D;.
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
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs727504604; hg19: chr2-179325090;