2-178451030-T-G

Position:

chr2-178451030-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001316362.2(PRKRA):c.-449A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,336,412 control chromosomes in the GnomAD database, including 6,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 0 hom., cov: 34)

Exomes 𝑓: 0.13 ( 6399 hom. )

Consequence

PRKRA
NM_001316362.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.533

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:

PRKRA (HGNC:):

PRKRA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021001399).

BP6

Variant 2-178451030-T-G is Benign according to our data. Variant chr2-178451030-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 332635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178451030-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKRA	NM_003690.5 linkuse as main transcript	c.1A>C	p.Met1?	initiator_codon_variant	1/8	ENST00000325748.9	NP_003681.1	O75569-1
PRKRA	NM_001316362.2 linkuse as main transcript	c.-449A>C		5_prime_UTR_premature_start_codon_gain_variant	1/9		NP_001303291.1	B4DJC7
PRKRA	XM_047446138.1 linkuse as main transcript	c.1A>C	p.Met1?	initiator_codon_variant	1/6		XP_047302094.1
PRKRA	NM_001316362.2 linkuse as main transcript	c.-449A>C		5_prime_UTR_variant	1/9		NP_001303291.1	B4DJC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748.9 linkuse as main transcript	c.1A>C	p.Met1?	initiator_codon_variant	1/8	1	NM_003690.5	ENSP00000318176.4		O75569-1

Frequencies

GnomAD3 genomes

AF:

0.0474

AC:

5848

AN:

123394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.0745

Gnomad AMR

AF:

0.0503

Gnomad ASJ

AF:

0.0882

Gnomad EAS

AF:

0.0306

Gnomad SAS

AF:

0.0567

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.0992

Gnomad NFE

AF:

0.0601

Gnomad OTH

AF:

0.0452

GnomAD3 exomes

AF:

0.257

AC:

41222

AN:

160416

Hom.:

6543

AF XY:

0.255

AC XY:

22426

AN XY:

87862

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.262

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.256

Gnomad NFE exome

AF:

0.297

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.134

AC:

162052

AN:

1212914

Hom.:

6399

Cov.:

AF XY:

0.134

AC XY:

80350

AN XY:

601090

show subpopulations

Gnomad4 AFR exome

AF:

0.0768

Gnomad4 AMR exome

AF:

0.237

Gnomad4 ASJ exome

AF:

0.183

Gnomad4 EAS exome

AF:

0.0758

Gnomad4 SAS exome

AF:

0.119

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.133

Gnomad4 OTH exome

AF:

0.128

GnomAD4 genome

AF:

0.0474

AC:

5851

AN:

123498

Hom.:

Cov.:

AF XY:

0.0461

AC XY:

2786

AN XY:

60438

show subpopulations

Gnomad4 AFR

AF:

0.0245

Gnomad4 AMR

AF:

0.0504

Gnomad4 ASJ

AF:

0.0882

Gnomad4 EAS

AF:

0.0307

Gnomad4 SAS

AF:

0.0569

Gnomad4 FIN

AF:

0.0513

Gnomad4 NFE

AF:

0.0601

Gnomad4 OTH

AF:

0.0446

Alfa

AF:

0.154

Hom.:

ExAC

AF:

0.383

AC:

31303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dystonia 16

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 09, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 354/2178=16.25% -

Hearing loss, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dystonic disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.11

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.77

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.29

MutPred

0.92

Loss of catalytic residue at M1 (P = 0.0205);

ClinPred

0.14

GERP RS

3.3

Varity_R

0.94

gMVP

0.44

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