2-178451558-C-T

Variant names:

• chr2-178451558-C-T
• rs555344314
• NM_001042702.5:c.-234C>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.-234C>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 0.00143 in 154,756 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: PJVK NM_001042702.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0160
• 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=-0.77).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00144 (219/152246) while in subpopulation SAS AF = 0.022 (106/4822). AF 95% confidence interval is 0.0186. There are 5 homozygotes in GnomAd4. There are 121 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.-234C>T		5_prime_UTR	Exon 1 of 7	NP_001036167.1	Q0ZLH3
	PJVK	NM_001353777.1		c.-546C>T		5_prime_UTR	Exon 1 of 7	NP_001340706.1	A0PK15
	PJVK	NM_001353775.2		c.-283C>T		upstream_gene	N/A	NP_001340704.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PJVK	ENST00000644580.2	MANE Select	c.-234C>T		5_prime_UTR	Exon 1 of 7	ENSP00000495855.2	Q0ZLH3
	PJVK	ENST00000970493.1		c.-346C>T		5_prime_UTR	Exon 1 of 8	ENSP00000640552.1
	PJVK	ENST00000642492.1		c.-769C>T		5_prime_UTR	Exon 1 of 8	ENSP00000496267.1	A0PK15

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152128 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00120 AC: 3 AN: 2510 Hom.: 0 Cov.: 3 AF XY: 0.000611 AC XY: 1 AN XY: 1636

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40

American (AMR) AF: 0.00 AC: 0 AN: 16

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22

East Asian (EAS) AF: 0.00 AC: 0 AN: 66

South Asian (SAS) AF: 0.00621 AC: 2 AN: 322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 14

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1898

Other (OTH) AF: 0.0106 AC: 1 AN: 94

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0186682), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152246 Hom.: 5 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74448

African (AFR) AF: 0.000168 AC: 7 AN: 41578

American (AMR) AF: 0.00150 AC: 23 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 67988

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

Alfa AF: 0.000636 Hom.: 0

Bravo AF: 0.000710

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 59 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.9
DANN	Benign	0.76
PhyloP100		0.016
PromoterAI		0.0033	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: rs555344314; hg19: chr2-179316285;