chr2-178447566-G-C

Variant names:

• chr2-178447566-G-C
• rs1311237497
• NM_003690.5:c.256C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003690.5(PRKRA):​c.256C>G​(p.Leu86Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PRKRA NM_003690.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12016064).

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.256C>G	p.Leu86Val	missense	Exon 3 of 8	NP_003681.1
	PRKRA	NM_001139517.1		c.223C>G	p.Leu75Val	missense	Exon 2 of 7	NP_001132989.1
	PRKRA	NM_001139518.1		c.181C>G	p.Leu61Val	missense	Exon 3 of 8	NP_001132990.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKRA	ENST00000325748.9	TSL:1 MANE Select	c.256C>G	p.Leu86Val	missense	Exon 3 of 8	ENSP00000318176.4
	PRKRA	ENST00000432031.6	TSL:1	c.223C>G	p.Leu75Val	missense	Exon 2 of 7	ENSP00000393883.2
	PRKRA	ENST00000487082.5	TSL:1	c.181C>G	p.Leu61Val	missense	Exon 3 of 8	ENSP00000430604.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251404 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461786 Hom.: 0 Cov.: 48 AF XY: 0.00000550 AC XY: 4 AN XY: 727192

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000249833), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 36

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.23	N
PhyloP100		1.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.49	T
Polyphen		0.016	B
Vest4		0.24
MutPred		0.36		Loss of solvent accessibility (P = 0.0045)
MVP		0.64
MPC		0.70
ClinPred		0.13	T
GERP RS		2.3
Varity_R		0.028
gMVP		0.21
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1311237497; hg19: chr2-179312293;