chr2-178432255-C-CTATATCCAAATA

Position:

• chr2-178432255-C-CTATATCCAAATA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_003690.5(PRKRA):​c.785-2_785-1insTATTTGGATATA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00174 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0072 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKRA NM_003690.5 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKRA	NM_003690.5	c.785-2_785-1insTATTTGGATATA		splice_acceptor_variant, intron_variant		ENST00000325748.9	NP_003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKRA	ENST00000325748.9	c.785-2_785-1insTATTTGGATATA		splice_acceptor_variant, intron_variant		1	NM_003690.5	ENSP00000318176.4

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152042 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00239

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00718 AC: 10430 AN: 1453216 Hom.: 0 Cov.: 56 AF XY: 0.00685 AC XY: 4955 AN XY: 723014

Gnomad4 AFR exome AF: 0.00390

Gnomad4 AMR exome AF: 0.00694

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00242

Gnomad4 SAS exome AF: 0.00332

Gnomad4 FIN exome AF: 0.00304

Gnomad4 NFE exome AF: 0.00813

Gnomad4 OTH exome AF: 0.00557

GnomAD4 genome AF: 0.00174 AC: 264 AN: 152160 Hom.: 0 Cov.: 35 AF XY: 0.00164 AC XY: 122 AN XY: 74384

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00480 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs751875722; hg19: chr2-179296982;