rs188208530

Positions:

• chr2-178436139-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003690.5(PRKRA):​c.784+6A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 796,824 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0054 (12 hom.)
• Consequence: PRKRA NM_003690.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001641
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0420

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-178436139-T-A is Benign according to our data. Variant chr2-178436139-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 425237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178436139-T-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKRA	NM_003690.5	c.784+6A>T		splice_donor_region_variant, intron_variant		ENST00000325748.9
CHROMR	NR_110204.1	n.965+2664T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKRA	ENST00000325748.9	c.784+6A>T		splice_donor_region_variant, intron_variant		1	NM_003690.5	P1
CHROMR	ENST00000453026.7	n.989+2664T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 248 AN: 83058 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000537

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00125

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000802

Gnomad MID AF: 0.00549

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.00353

GnomAD3 exomes AF: 0.00263 AC: 452 AN: 172034 Hom.: 1 AF XY: 0.00255 AC XY: 239 AN XY: 93564

Gnomad AFR exome AF: 0.000639

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.000683

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000472

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00540 AC: 3852 AN: 713694 Hom.: 12 Cov.: 29 AF XY: 0.00516 AC XY: 1866 AN XY: 361606

Gnomad4 AFR exome AF: 0.000384

Gnomad4 AMR exome AF: 0.00307

Gnomad4 ASJ exome AF: 0.000983

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000861

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00692

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.00298 AC: 248 AN: 83130 Hom.: 0 Cov.: 22 AF XY: 0.00252 AC XY: 103 AN XY: 40872

Gnomad4 AFR AF: 0.000536

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00125

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000802

Gnomad4 NFE AF: 0.00617

Gnomad4 OTH AF: 0.00347

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00197

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PRKRA: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	- -

Dystonia 16 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.014
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

LitVar

Other links and lift over

dbSNP: rs188208530; hg19: chr2-179300866;