NM_003690.5:c.131T>G

Variant names:

• chr2-178450346-A-C
• rs1553599437
• NM_003690.5:c.131T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003690.5(PRKRA):​c.131T>G​(p.Met44Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M44T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 35)
• Consequence: PRKRA NM_003690.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.10
• 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]

PRKRA Gene-Disease associations (from GenCC):

• dystonia 16

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKRA	NM_003690.5	MANE Select	c.131T>G	p.Met44Arg	missense	Exon 2 of 8	NP_003681.1
	PRKRA	NM_001139517.1		c.98T>G	p.Met33Arg	missense	Exon 1 of 7	NP_001132989.1
	PRKRA	NM_001139518.1		c.56T>G	p.Met19Arg	missense	Exon 2 of 8	NP_001132990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKRA	ENST00000325748.9	TSL:1 MANE Select	c.131T>G	p.Met44Arg	missense	Exon 2 of 8	ENSP00000318176.4
	PRKRA	ENST00000432031.6	TSL:1	c.98T>G	p.Met33Arg	missense	Exon 1 of 7	ENSP00000393883.2
	PRKRA	ENST00000487082.5	TSL:1	c.56T>G	p.Met19Arg	missense	Exon 2 of 8	ENSP00000430604.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.052
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.77	N
PhyloP100		5.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.035	D
Polyphen		0.47	P
Vest4		0.66
MutPred		0.70		Gain of methylation at K45 (P = 0.0304)
MVP		0.77
MPC		1.5
ClinPred		0.88	D
GERP RS		5.8
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.55
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553599437; hg19: chr2-179315073;