2-178436139-T-G

Variant names:

• chr2-178436139-T-G
• rs188208530
• NM_003690.5:c.784+6A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003690.5(PRKRA):​c.784+6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 713,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: PRKRA NM_003690.5 splice_region, intron
• Scores: Splicing: ADA: 0.0009594
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• 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]

CHROMR (HGNC:54059): (cholesterol induced regulator of metabolism RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

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.784+6A>C		splice_region intron	N/A	NP_003681.1	O75569-1
	PRKRA	NM_001139517.1		c.751+6A>C		splice_region intron	N/A	NP_001132989.1	O75569-2
	PRKRA	NM_001139518.1		c.709+6A>C		splice_region intron	N/A	NP_001132990.1	O75569-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKRA	ENST00000325748.9	TSL:1 MANE Select	c.784+6A>C		splice_region intron	N/A	ENSP00000318176.4	O75569-1
	PRKRA	ENST00000432031.6	TSL:1	c.751+6A>C		splice_region intron	N/A	ENSP00000393883.2	O75569-2
	PRKRA	ENST00000487082.5	TSL:1	c.709+6A>C		splice_region intron	N/A	ENSP00000430604.1	O75569-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000560 AC: 4 AN: 713734 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361620

African (AFR) AF: 0.00 AC: 0 AN: 23416

American (AMR) AF: 0.00 AC: 0 AN: 20182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13224

East Asian (EAS) AF: 0.00 AC: 0 AN: 18996

South Asian (SAS) AF: 0.00 AC: 0 AN: 53452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3200

European-Non Finnish (NFE) AF: 0.00000773 AC: 4 AN: 517352

Other (OTH) AF: 0.00 AC: 0 AN: 31306

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.042

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00096
dbscSNV1_RF	Benign	0.054
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: rs188208530; hg19: chr2-179300866;