2-178431442-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003690.5(PRKRA):c.*655T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.05

Genes affected

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]

CHROMR (HGNC:54059): (cholesterol induced regulator of metabolism RNA)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0372 (22/592) while in subpopulation EAS AF= 0.25 (1/4). AF 95% confidence interval is 0.0214. There are 0 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKRA	NM_003690.5	c.*655T>C		3_prime_UTR_variant	8/8	ENST00000325748.9
CHROMR	NR_110204.1	n.871+553A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKRA	ENST00000325748.9	c.*655T>C		3_prime_UTR_variant	8/8	1	NM_003690.5	P1
CHROMR	ENST00000453026.7	n.895+553A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7642 AN: 114834 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0953

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.0581

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0787

Gnomad OTH AF: 0.0784

GnomAD4 exome AF: 0.0372 AC: 22 AN: 592 Hom.: 0 Cov.: 0 AF XY: 0.0414 AC XY: 13 AN XY: 314

Gnomad4 AMR exome AF: 0.0492

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.0306

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0666 AC: 7653 AN: 114922 Hom.: 0 Cov.: 33 AF XY: 0.0662 AC XY: 3752 AN XY: 56706

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.0956

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.0967

Gnomad4 SAS AF: 0.0580

Gnomad4 FIN AF: 0.0606

Gnomad4 NFE AF: 0.0787

Gnomad4 OTH AF: 0.0773

Alfa AF: 0.152 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.30
Dann	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs4533501; hg19: chr2-179296169; COSMIC: COSV105214596; COSMIC: COSV105214596;