2-178432104-C-T

Variant names:

• chr2-178432104-C-T
• NM_003690.5:c.935G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003690.5(PRKRA):​c.935G>A​(p.Arg312Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: PRKRA NM_003690.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048463225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKRA	NM_003690.5	c.935G>A	p.Arg312Lys	missense_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.935G>A	p.Arg312Lys	missense_variant	Exon 8 of 8	1	NM_003690.5	ENSP00000318176.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.935G>A (p.R312K) alteration is located in exon 8 (coding exon 8) of the PRKRA gene. This alteration results from a G to A substitution at nucleotide position 935, causing the arginine (R) at amino acid position 312 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.054	T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.12	N;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.069
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0060	B;.;B
Vest4		0.10
MutPred		0.23		Gain of methylation at R312 (P = 0.0121);.;.;
MVP		0.59
MPC		0.69
ClinPred		0.10	T
GERP RS		3.4
Varity_R		0.051
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-179296831;