2-178432094-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003690.5(PRKRA):c.*3C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 150,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (0 hom., cov: 35)
  • Exomes 𝑓: 0.26 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0510

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-178432094-G-A is Benign according to our data. Variant chr2-178432094-G-A is described in ClinVar as [Benign]. Clinvar id is 332620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178432094-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKRA	NM_003690.5	c.*3C>T		3_prime_UTR_variant	8/8	ENST00000325748.9
CHROMR	NR_110204.1	n.871+1205G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKRA	ENST00000325748.9	c.*3C>T		3_prime_UTR_variant	8/8	1	NM_003690.5	P1
CHROMR	ENST00000453026.7	n.895+1205G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.225 AC: 33833 AN: 150292 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.228

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.263 AC: 378902 AN: 1440070 Hom.: 2 Cov.: 46 AF XY: 0.259 AC XY: 185824 AN XY: 716690

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.287

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.225 AC: 33855 AN: 150408 Hom.: 0 Cov.: 35 AF XY: 0.223 AC XY: 16375 AN XY: 73436

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.226

Alfa AF: 0.135 Hom.: 1

Asia WGS AF: 0.210 AC: 730 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

- -

Dystonia 16 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.0
Dann	Benign	0.60

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: rs3997876; hg19: chr2-179296821; COSMIC: COSV57869240; COSMIC: COSV57869240;