rs150679361

chr2-178432244-G-Achr2-178432244-G-Cchr2-178432244-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003690.5(PRKRA):c.795C>T(p.Ser265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00953 in 1,613,398 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 35)
  • Exomes 𝑓: 0.0098 (52 hom.)
• Consequence: PRKRA NM_003690.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178432244-G-A is Benign according to our data. Variant chr2-178432244-G-A is described in ClinVar as [Benign]. Clinvar id is 469612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178432244-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKRA	NM_003690.5	c.795C>T	p.Ser265=	synonymous_variant	8/8	ENST00000325748.9
CHROMR	NR_110204.1	n.872-1138G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKRA	ENST00000325748.9	c.795C>T	p.Ser265=	synonymous_variant	8/8	1	NM_003690.5	P1
CHROMR	ENST00000453026.7	n.896-1138G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152222 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00777 AC: 1950 AN: 250906 Hom.: 8 AF XY: 0.00782 AC XY: 1061 AN XY: 135712

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00980 AC: 14325 AN: 1461058 Hom.: 52 Cov.: 58 AF XY: 0.00966 AC XY: 7019 AN XY: 726872

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00599

Gnomad4 FIN exome AF: 0.00648

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00908

GnomAD4 genome AF: 0.00685 AC: 1044 AN: 152340 Hom.: 6 Cov.: 35 AF XY: 0.00642 AC XY: 478 AN XY: 74496

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.00584

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00996

Alfa AF: 0.00852 Hom.: 1

Bravo AF: 0.00672

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.0103

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PRKRA: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	This variant is associated with the following publications: (PMID: 23814535, 18420150) -

Dystonia 16 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	11
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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;