2-178451030-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_ModerateBP6_Very_StrongBS2

The NM_003690.5(PRKRA):c.1A>C(p.Met1?) variant causes a initiator codon 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_003690.5 initiator_codon

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.533

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

dystonia 16
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet

PRKRA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 26 codons. Genomic position: 178450401. Lost 0.081 part of the original CDS.

BP6

Variant 2-178451030-T-G is Benign according to our data. Variant chr2-178451030-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 332635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 6399 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKRA	NM_003690.5 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 8	ENST00000325748.9	NP_003681.1	O75569-1
PRKRA	NM_001316362.2 link	c.-449A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9		NP_001303291.1	B4DJC7
PRKRA	XM_047446138.1 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6		XP_047302094.1
PRKRA	NM_001316362.2 link	c.-449A>C		5_prime_UTR_variant	Exon 1 of 9		NP_001303291.1	B4DJC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748.9 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.257

AC:

41222

AN:

160416

AF XY:

0.255

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0768

AC:

2136

AN:

27822

American (AMR)

AF:

0.237

AC:

8691

AN:

36652

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

4018

AN:

21974

East Asian (EAS)

AF:

0.0758

AC:

2528

AN:

33344

South Asian (SAS)

AF:

0.119

AC:

8488

AN:

71408

European-Finnish (FIN)

AF:

0.130

AC:

4545

AN:

35036

Middle Eastern (MID)

AF:

0.184

AC:

920

AN:

5000

European-Non Finnish (NFE)

AF:

0.133

AC:

124204

AN:

930764

Other (OTH)

AF:

0.128

AC:

6522

AN:

50914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.305

Heterozygous variant carriers

12660

25320

37980

50640

63300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4796

9592

14388

19184

23980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0474

AC:

5851

AN:

123498

Hom.:

Cov.:

AF XY:

0.0461

AC XY:

2786

AN XY:

60438

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0245

AC:

894

AN:

36460

American (AMR)

AF:

0.0504

AC:

598

AN:

11858

Ashkenazi Jewish (ASJ)

AF:

0.0882

AC:

222

AN:

2516

East Asian (EAS)

AF:

0.0307

AC:

139

AN:

4530

South Asian (SAS)

AF:

0.0569

AC:

218

AN:

3830

European-Finnish (FIN)

AF:

0.0513

AC:

441

AN:

8590

Middle Eastern (MID)

AF:

0.0855

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0601

AC:

3187

AN:

53016

Other (OTH)

AF:

0.0446

AC:

AN:

1726

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

735

1470

2205

2940

3675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jul 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dystonic disorder

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

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

PhyloP100

0.53

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

PromoterAI

-0.33

Neutral

(source)

Varity_R

0.94

gMVP

0.44

Mutation Taster

=124/76

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over