chr2-178432178-G-A

Variant names:

• chr2-178432178-G-A
• rs116833881
• NM_003690.5:c.861C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_003690.5(PRKRA):​c.861C>T​(p.Ser287Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,613,034 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 benign (★★). Synonymous variant affecting the same amino acid position (i.e. S287S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0092 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: PRKRA NM_003690.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.81

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-178432178-G-A is Benign according to our data. Variant chr2-178432178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 518334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178432178-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00922 (1403/152098) while in subpopulation AFR AF= 0.0294 (1217/41368). AF 95% confidence interval is 0.028. There are 0 homozygotes in gnomad4. There are 646 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKRA	NM_003690.5	c.861C>T	p.Ser287Ser	synonymous_variant	Exon 8 of 8	ENST00000325748.9	NP_003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748.9	c.861C>T	p.Ser287Ser	synonymous_variant	Exon 8 of 8	1	NM_003690.5	ENSP00000318176.4

Frequencies

GnomAD3 genomes AF: 0.00919 AC: 1396 AN: 151978 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00234 AC: 587 AN: 250752 Hom.: 0 AF XY: 0.00189 AC XY: 256 AN XY: 135598

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00233 AC: 3406 AN: 1460936 Hom.: 0 Cov.: 60 AF XY: 0.00211 AC XY: 1534 AN XY: 726770

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.00383

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00922 AC: 1403 AN: 152098 Hom.: 0 Cov.: 35 AF XY: 0.00869 AC XY: 646 AN XY: 74362

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00203 Hom.: 0

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000949

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia 16 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 17, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 15, 2021	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs116833881; hg19: chr2-179296905; COSMIC: COSV100359548; COSMIC: COSV100359548;