NM_003690.5:c.665C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B.

PP5_Very_StrongBP4

The NM_003690.5(PRKRA):c.665C>T(p.Pro222Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000818 in 1,613,684 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 pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 36)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PRKRA
NM_003690.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.99

Publications

25 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 links:

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

CHROMR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PP5

Variant 2-178436264-G-A is Pathogenic according to our data. Variant chr2-178436264-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.10131222). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKRA	NM_003690.5 link	c.665C>T	p.Pro222Leu	missense_variant	Exon 7 of 8	ENST00000325748.9	NP_003681.1	O75569-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748.9 link	c.665C>T	p.Pro222Leu	missense_variant	Exon 7 of 8	1	NM_003690.5	ENSP00000318176.4		O75569-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000995

AC:

AN:

251284

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461468

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727074

show subpopulations

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

African (AFR)

AF:

0.0000896

AC:

AN:

33468

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

1111722

Other (OTH)

AF:

0.0000994

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.378

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000920

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000829

Hom.:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dystonia 16

Pathogenic:8

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 222 of the PRKRA protein (p.Pro222Leu). This variant is present in population databases (rs121434410, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive dystonia (PMID: 18243799, 25142429, 26990861). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6346). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRKRA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRKRA function (PMID: 26231208). For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Genomics England Pilot Project, Genomics England

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 31, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest no damaging effect of the variant on gene or gene product [REVEL: 0.35 (<0.4); 3Cnet: 0.02 (<0.15, specificity 0.78 and negative predicitive value 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006346 /PMID: 18243799 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18243799). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18243799). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

May 11, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

PRKRA-related disorder

Pathogenic:1

Feb 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PRKRA c.665C>T variant is predicted to result in the amino acid substitution p.Pro222Leu. This variant was reported in the homozygous and compound heterozygous state in individuals with dystonia-parkinsonism and has been shown to segregate with disease in families (Camargos et al. 2008. PubMed ID: 18243799; Zech et al. 2014. PubMed ID: 25142429; Quadri et al. 2016. PubMed ID: 26990861; Dos Santos et al. 2017. PubMed ID: 29279192; Molloy et al. 2022. PubMed ID: 36186440). This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD . In vitro experimental studies suggest this variant impacts protein function (Vaughn et al. 2015. PubMed ID: 26231208; Burnett et al. 2020. PubMed ID: 33049316). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Dec 03, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (PMID: 26231208); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22194846, 26231208, 34758253, 18243799, 25737287, 29279192, 25142429, 26990861, 31216405, 33049316, 31589614, 33606314) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.56

T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-0.34

N;.;.

PhyloP100

4.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.75

N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.048

D;D;D

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.30

MVP

0.78

MPC

0.69

ClinPred

0.040

GERP RS

3.9

Varity_R

0.077

gMVP

0.27

Mutation Taster

=14/86

disease causing (ClinVar)

(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