NM_003690.5:c.861C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

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 Uncertain significance.

• 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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0237) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).
• 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 VariationId is 518334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003690.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKRA	NM_003690.5	MANE Select	c.861C>T	p.Ser287Ser	synonymous	Exon 8 of 8	NP_003681.1	O75569-1
	PRKRA	NM_001139517.1		c.828C>T	p.Ser276Ser	synonymous	Exon 7 of 7	NP_001132989.1	O75569-2
	PRKRA	NM_001139518.1		c.786C>T	p.Ser262Ser	synonymous	Exon 8 of 8	NP_001132990.1	O75569-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKRA	ENST00000325748.9	TSL:1 MANE Select	c.861C>T	p.Ser287Ser	synonymous	Exon 8 of 8	ENSP00000318176.4	O75569-1
	PRKRA	ENST00000432031.6	TSL:1	c.828C>T	p.Ser276Ser	synonymous	Exon 7 of 7	ENSP00000393883.2	O75569-2
	PRKRA	ENST00000487082.5	TSL:1	c.786C>T	p.Ser262Ser	synonymous	Exon 8 of 8	ENSP00000430604.1	O75569-3

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

GnomAD2 exomes AF: 0.00234 AC: 587 AN: 250752 AF XY: 0.00189

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 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

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

African (AFR) AF: 0.0251 AC: 833 AN: 33238

American (AMR) AF: 0.00383 AC: 171 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86246

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53412

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.00197 AC: 2195 AN: 1111480

Other (OTH) AF: 0.00287 AC: 173 AN: 60362

⚠️ 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.

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

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

African (AFR) AF: 0.0294 AC: 1217 AN: 41368

American (AMR) AF: 0.00510 AC: 78 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68036

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

⚠️ 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.

Alfa AF: 0.00203 Hom.: 0

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Dystonia 16 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.73
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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