2-178432244-G-T

Position:

• chr2-178432244-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000325748.9(PRKRA):​c.795C>A​(p.Ser265Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S265S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKRA ENST00000325748.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.128

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKRA	NM_003690.5	c.795C>A	p.Ser265Arg	missense_variant	8/8	ENST00000325748.9	NP_003681.1
CHROMR	NR_110204.1	n.872-1138G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748.9	c.795C>A	p.Ser265Arg	missense_variant	8/8	1	NM_003690.5	ENSP00000318176	P1
CHROMR	ENST00000453026.7	n.896-1138G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461842 Hom.: 0 Cov.: 58 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with idiopathic dystonia (PMID: 29279192). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 265 of the PRKRA protein (p.Ser265Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.53	N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.30
MutPred		0.59		Gain of solvent accessibility (P = 0.0584);.;.;
MVP		0.89
MPC		1.8
ClinPred		0.98	D
GERP RS		1.4
Varity_R		0.60
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150679361; hg19: chr2-179296971;