2-178431897-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM2 BP4_Moderate BP6_Very_Strong BS1

The NM_003690.5(PRKRA):c.*200G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0202 in 665,466 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (0 hom., cov: 35)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.25

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 -12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-178431897-C-T is Benign according to our data. Variant chr2-178431897-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 894034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0195 (2954/151868) while in subpopulation NFE AF= 0.0216 (1463/67858). AF 95% confidence interval is 0.0206. There are 0 homozygotes in gnomad4. There are 1430 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKRA	NM_003690.5	c.*200G>A		3_prime_UTR_variant	8/8	ENST00000325748.9
CHROMR	NR_110204.1	n.871+1008C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKRA	ENST00000325748.9	c.*200G>A		3_prime_UTR_variant	8/8	1	NM_003690.5	P1
CHROMR	ENST00000453026.7	n.895+1008C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2954 AN: 151750 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0284

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0204 AC: 10500 AN: 513598 Hom.: 0 Cov.: 6 AF XY: 0.0204 AC XY: 5506 AN XY: 270308

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00851

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.00807

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0195 AC: 2954 AN: 151868 Hom.: 0 Cov.: 35 AF XY: 0.0193 AC XY: 1430 AN XY: 74248

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.00622

Gnomad4 ASJ AF: 0.0284

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0223 Hom.: 0

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Dystonia 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.31
Cadd	Benign	15
Dann	Benign	0.83

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: rs141995027; hg19: chr2-179296624;