rs727504946

Positions:

• chr2-178453604-C-G
• chr2-178453604-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.390

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 179555.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178453604-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PJVK	NM_001042702.5	c.195C>G	p.Asp65Glu	missense_variant	2/7	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2	c.195C>G	p.Asp65Glu	missense_variant	2/7		NM_001042702.5	ENSP00000495855.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460468 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 27, 2014

Asp65Glu in exon 2 of DFNB59: This variant is not expected to have clinical sig nificance because the amino acid residue at this position is not well conserved, with several species (birds, reptiles and fish) including one mammal (elephant shrew) having this variant (Glu) at this position, and computational analyses (a mino acid biochemical properties, conservation, SIFT, PolyPhen-2, AlignGVGD) sug gest this variant may not impact the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.087	T;T;.;T
Eigen	Benign	0.017
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	.;.;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.17	N;N;.;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	.;N;.;N
REVEL	Benign	0.059
Sift	Benign	0.31	.;T;.;T
Sift4G	Benign	1.0	.;T;.;T
Polyphen		0.0070	B;B;.;B
Vest4		0.10, 0.077
MutPred		0.39		Gain of solvent accessibility (P = 0.0503);Gain of solvent accessibility (P = 0.0503);Gain of solvent accessibility (P = 0.0503);Gain of solvent accessibility (P = 0.0503);
MVP		0.048
MPC		0.099
ClinPred		0.26	T
GERP RS		4.3
Varity_R		0.087
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs727504946; hg19: chr2-179318331;