Variant 2-178431442-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.05

Variant links:

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]

PRKRA links:

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

CHROMR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.*655T>C		3_prime_UTR_variant	8/8	ENST00000325748.9
CHROMR	NR_110204.1 linkuse as main transcript	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 linkuse as main transcript	c.*655T>C		3_prime_UTR_variant	8/8	1	NM_003690.5	P1	O75569-1
CHROMR	ENST00000453026.7 linkuse as main transcript	n.895+553A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

7642

AN:

114834

Hom.:

Cov.:

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:

AN:

592

Hom.:

Cov.:

AF XY:

0.0414

AC XY:

AN XY:

314

show subpopulations

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.:

Cov.:

AF XY:

0.0662

AC XY:

3752

AN XY:

56706

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over