rs121434410

Variant names:

• chr2-178436264-G-A
• rs121434410
• NM_003690.5:c.665C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

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 (★★). ClinVar reports functional evidence for this variant: "SCV002148103: Experimental studies have shown that this missense change affects PRKRA function (PMID:26231208)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: PRKRA NM_003690.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.99
• Publications: 25 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: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002148103: Experimental studies have shown that this missense change affects PRKRA function (PMID: 26231208).; SCV002028673: Published functional studies demonstrate a damaging effect (PMID: 26231208); SCV004730469: "In vitro experimental studies suggest this variant impacts protein function" (Vaughn et al. 2015. PubMed ID: 26231208; Burnett et al. 2020. PubMed ID: 33049316).
• PP5: Variant 2-178436264-G-A is Pathogenic according to our data. Variant chr2-178436264-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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.

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.665C>T	p.Pro222Leu	missense	Exon 7 of 8	NP_003681.1	O75569-1
	PRKRA	NM_001139517.1		c.632C>T	p.Pro211Leu	missense	Exon 6 of 7	NP_001132989.1	O75569-2
	PRKRA	NM_001139518.1		c.590C>T	p.Pro197Leu	missense	Exon 7 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.665C>T	p.Pro222Leu	missense	Exon 7 of 8	ENSP00000318176.4	O75569-1
	PRKRA	ENST00000432031.6	TSL:1	c.632C>T	p.Pro211Leu	missense	Exon 6 of 7	ENSP00000393883.2	O75569-2
	PRKRA	ENST00000487082.5	TSL:1	c.590C>T	p.Pro197Leu	missense	Exon 7 of 8	ENSP00000430604.1	O75569-3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152216 Hom.: 0 Cov.: 36

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: 25 AN: 251284 AF XY: 0.0000663

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.: 0 Cov.: 39 AF XY: 0.0000646 AC XY: 47 AN XY: 727074

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

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000882 AC: 98 AN: 1111722

Other (OTH) AF: 0.0000994 AC: 6 AN: 60374

⚠️ 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: 0.0000920 AC: 14 AN: 152216 Hom.: 0 Cov.: 36 AF XY: 0.000108 AC XY: 8 AN XY: 74362

African (AFR) AF: 0.0000724 AC: 3 AN: 41452

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000829 Hom.: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Dystonia 16 (9)
1	-	-	not provided (1)
1	-	-	PRKRA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.34	N
PhyloP100		4.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.35
Sift	Benign	0.048	D
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.30
MVP		0.78
MPC		0.69
ClinPred		0.040	T
GERP RS		3.9
Varity_R		0.077
gMVP		0.27
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs121434410; hg19: chr2-179300991;