rs3997881

Variant names:

• chr2-178431544-T-C
• rs3997881
• NM_003690.5:c.*553A>G

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.*553A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,260 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (0 hom., cov: 34)
  • Exomes 𝑓: 0.33 (1 hom.)
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.160
• Publications: 1 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: Variant has high frequency in the MID (0.326) population. However there is too low homozygotes in high coverage region: (expected more than 1834, got 1).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.*553A>G		3_prime_UTR	Exon 8 of 8	NP_003681.1	O75569-1
	PRKRA	NM_001139517.1		c.*553A>G		3_prime_UTR	Exon 7 of 7	NP_001132989.1	O75569-2
	PRKRA	NM_001139518.1		c.*553A>G		3_prime_UTR	Exon 8 of 8	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.*553A>G		3_prime_UTR	Exon 8 of 8	ENSP00000318176.4	O75569-1
	PRKRA	ENST00000914393.1		c.*553A>G		3_prime_UTR	Exon 8 of 8	ENSP00000584452.1
	PRKRA	ENST00000677981.1		c.*553A>G		3_prime_UTR	Exon 6 of 6	ENSP00000503536.1	A0A7I2V3J2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 31656 AN: 146106 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.325 AC: 1638 AN: 5038 Hom.: 1 Cov.: 0 AF XY: 0.320 AC XY: 839 AN XY: 2622

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

African (AFR) AF: 0.250 AC: 2 AN: 8

American (AMR) AF: 0.356 AC: 389 AN: 1094

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 21 AN: 46

East Asian (EAS) AF: 0.381 AC: 93 AN: 244

South Asian (SAS) AF: 0.277 AC: 122 AN: 440

European-Finnish (FIN) AF: 0.174 AC: 64 AN: 368

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.333 AC: 884 AN: 2658

Other (OTH) AF: 0.348 AC: 62 AN: 178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.217 AC: 31678 AN: 146222 Hom.: 0 Cov.: 34 AF XY: 0.214 AC XY: 15299 AN XY: 71388

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

African (AFR) AF: 0.151 AC: 6070 AN: 40158

American (AMR) AF: 0.258 AC: 3778 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 870 AN: 3332

East Asian (EAS) AF: 0.270 AC: 1335 AN: 4942

South Asian (SAS) AF: 0.207 AC: 950 AN: 4588

European-Finnish (FIN) AF: 0.194 AC: 1970 AN: 10180

Middle Eastern (MID) AF: 0.198 AC: 57 AN: 288

European-Non Finnish (NFE) AF: 0.244 AC: 15930 AN: 65172

Other (OTH) AF: 0.216 AC: 439 AN: 2028

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.222 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia 16 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.73
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3997881; hg19: chr2-179296271; COSMIC: COSV105214598; COSMIC: COSV105214598;