chr2-178431784-C-T

Variant names:

• chr2-178431784-C-T
• rs3997879
• NM_003690.5:c.*313G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BA1

The NM_003690.5(PRKRA):​c.*313G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 371,174 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (0 hom., cov: 35)
  • Exomes 𝑓: 0.29 (9 hom.)
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-178431784-C-T is Benign according to our data. Variant chr2-178431784-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 332613.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKRA	NM_003690.5	c.*313G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000325748.9	NP_003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748	c.*313G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_003690.5	ENSP00000318176.4

Frequencies

GnomAD3 genomes AF: 0.225 AC: 33886 AN: 150366 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.290 AC: 63994 AN: 220690 Hom.: 9 Cov.: 0 AF XY: 0.284 AC XY: 33113 AN XY: 116714

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.349

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.303

GnomAD4 genome AF: 0.225 AC: 33909 AN: 150484 Hom.: 0 Cov.: 35 AF XY: 0.223 AC XY: 16406 AN XY: 73462

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.224

Alfa AF: 0.224 Hom.: 0

Asia WGS AF: 0.209 AC: 728 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dystonia 16 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3997879; hg19: chr2-179296511; COSMIC: COSV57868549; COSMIC: COSV57868549;