NM_003690.5:c.*655T>C

Variant names:

• chr2-178431442-A-G
• rs4533501
• NM_003690.5:c.*655T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003690.5(PRKRA):​c.*655T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.05
• Publications: 3 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

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.*655T>C		3_prime_UTR	Exon 8 of 8	NP_003681.1	O75569-1
	PRKRA	NM_001139517.1		c.*655T>C		3_prime_UTR	Exon 7 of 7	NP_001132989.1	O75569-2
	PRKRA	NM_001139518.1		c.*655T>C		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.*655T>C		3_prime_UTR	Exon 8 of 8	ENSP00000318176.4	O75569-1
	PRKRA	ENST00000914393.1		c.*655T>C		3_prime_UTR	Exon 8 of 8	ENSP00000584452.1
	PRKRA	ENST00000677981.1		c.*655T>C		3_prime_UTR	Exon 6 of 6	ENSP00000503536.1	A0A7I2V3J2

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 7642 AN: 114834 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0953

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.0581

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0787

Gnomad OTH AF: 0.0784

GnomAD4 exome AF: 0.0372 AC: 22 AN: 592 Hom.: 0 Cov.: 0 AF XY: 0.0414 AC XY: 13 AN XY: 314

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

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.0492 AC: 6 AN: 122

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AF: 0.0400 AC: 2 AN: 50

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0306 AC: 12 AN: 392

Other (OTH) AF: 0.00 AC: 0 AN: 18

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0666 AC: 7653 AN: 114922 Hom.: 0 Cov.: 33 AF XY: 0.0662 AC XY: 3752 AN XY: 56706

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

African (AFR) AF: 0.0357 AC: 1218 AN: 34070

American (AMR) AF: 0.0956 AC: 1059 AN: 11078

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 231 AN: 2482

East Asian (EAS) AF: 0.0967 AC: 353 AN: 3650

South Asian (SAS) AF: 0.0580 AC: 218 AN: 3756

European-Finnish (FIN) AF: 0.0606 AC: 507 AN: 8366

Middle Eastern (MID) AF: 0.0321 AC: 7 AN: 218

European-Non Finnish (NFE) AF: 0.0787 AC: 3863 AN: 49104

Other (OTH) AF: 0.0773 AC: 124 AN: 1604

⚠️ 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: 0.0908 Hom.: 0

ClinVar

ClinVar submissions

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	-0.95
CADD	Benign	0.30
DANN	Benign	0.36
PhyloP100		-1.0
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: rs4533501; hg19: chr2-179296169; COSMIC: COSV105214596; COSMIC: COSV105214596;