rs118203988

Variant names:

• chr2-178453570-C-T
• rs118203988
• NM_001042702.5:c.161C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001042702.5(PJVK):​c.161C>T​(p.Thr54Ile) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57
• Publications: 10 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 2-178453570-C-T is Pathogenic according to our data. Variant chr2-178453570-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1298.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PJVK	NM_001042702.5	c.161C>T	p.Thr54Ile	missense_variant	Exon 2 of 7	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2	c.161C>T	p.Thr54Ile	missense_variant	Exon 2 of 7		NM_001042702.5	ENSP00000495855.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 59 Pathogenic:1

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
LIST_S2	Benign	0.0	.;.;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M;M;.;M
PhyloP100		7.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.0	.;N;.;N
Sift	Pathogenic	0.0	.;T;.;T
Sift4G	Pathogenic	0.0	.;D;.;D
Vest4		0.0
ClinPred		0.99	D
GERP RS		6.1
PromoterAI		-0.018	Neutral
Varity_R		0.26
gMVP		0.74
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs118203988; hg19: chr2-179318297;