2-178451719-C-T

Variant names:

• chr2-178451719-C-T
• rs573551830
• NM_001042702.5:c.-73C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001042702.5(PJVK):​c.-73C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000868 in 965,614 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (11 hom.)
• Consequence: PJVK NM_001042702.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0610
• 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]

PRKRA (HGNC:9438): (protein activator of interferon induced protein kinase EIF2AK2) This gene encodes a protein kinase activated by double-stranded RNA which mediates the effects of interferon in response to viral infection. Mutations in this gene have been associated with dystonia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

PRKRA Gene-Disease associations (from GenCC):

• dystonia 16

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00145 (221/152338) while in subpopulation SAS AF = 0.0224 (108/4830). AF 95% confidence interval is 0.0189. There are 5 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042702.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PJVK	NM_001042702.5	MANE Select	c.-73C>T		5_prime_UTR	Exon 1 of 7	NP_001036167.1	Q0ZLH3
	PJVK	NM_001353775.2		c.-122C>T		5_prime_UTR	Exon 1 of 7	NP_001340704.1
	PJVK	NM_001353777.1		c.-385C>T		5_prime_UTR	Exon 1 of 7	NP_001340706.1	A0PK15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PJVK	ENST00000644580.2	MANE Select	c.-73C>T		5_prime_UTR	Exon 1 of 7	ENSP00000495855.2	Q0ZLH3
	PJVK	ENST00000970493.1		c.-185C>T		5_prime_UTR	Exon 1 of 8	ENSP00000640552.1
	PJVK	ENST00000642492.1		c.-608C>T		5_prime_UTR	Exon 1 of 8	ENSP00000496267.1	A0PK15

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152220 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000759 AC: 617 AN: 813276 Hom.: 11 Cov.: 14 AF XY: 0.000883 AC XY: 332 AN XY: 376142

African (AFR) AF: 0.000130 AC: 2 AN: 15392

American (AMR) AF: 0.00 AC: 0 AN: 958

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 6 AN: 5016

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3556

South Asian (SAS) AF: 0.0176 AC: 283 AN: 16050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 274

Middle Eastern (MID) AF: 0.00253 AC: 4 AN: 1580

European-Non Finnish (NFE) AF: 0.000321 AC: 239 AN: 743796

Other (OTH) AF: 0.00308 AC: 82 AN: 26654

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152338 Hom.: 5 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74486

African (AFR) AF: 0.000168 AC: 7 AN: 41586

American (AMR) AF: 0.00150 AC: 23 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000710

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 59 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.89
PhyloP100		0.061
PromoterAI		-0.054	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs573551830; hg19: chr2-179316446;