chr2-178431939-T-C

Position:

• chr2-178431939-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003690.5(PRKRA):​c.*158A>G 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 150,498 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (0 hom., cov: 35)
  • Exomes 𝑓: 0.29 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0240

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-178431939-T-C is Benign according to our data. Variant chr2-178431939-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 332618.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKRA	NM_003690.5	c.*158A>G		3_prime_UTR_variant	8/8	ENST00000325748.9
CHROMR	NR_110204.1	n.871+1050T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKRA	ENST00000325748.9	c.*158A>G		3_prime_UTR_variant	8/8	1	NM_003690.5	P1
CHROMR	ENST00000453026.7	n.895+1050T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.225 AC: 33886 AN: 150378 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.227

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.294 AC: 209244 AN: 711018 Hom.: 10 Cov.: 10 AF XY: 0.287 AC XY: 104959 AN XY: 366080

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.225 AC: 33910 AN: 150498 Hom.: 0 Cov.: 35 AF XY: 0.223 AC XY: 16407 AN XY: 73478

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.225

Alfa AF: 0.222 Hom.: 1

Asia WGS AF: 0.210 AC: 730 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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.0
DANN	Benign	0.87
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: rs3997877; hg19: chr2-179296666; COSMIC: COSV57868921; COSMIC: COSV57868921;