2-178431897-C-T

Variant names:

• chr2-178431897-C-T
• rs141995027
• NM_003690.5:c.*200G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_003690.5(PRKRA):​c.*200G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0202 in 665,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (0 hom., cov: 35)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: PRKRA NM_003690.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.25
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• PM2: Variant has high frequency in the MID (0.0221) population. However there is too low homozygotes in high coverage region: (expected more than 68, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-178431897-C-T is Benign according to our data. Variant chr2-178431897-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 894034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.*200G>A		3_prime_UTR	Exon 8 of 8	NP_003681.1	O75569-1
	PRKRA	NM_001139517.1		c.*200G>A		3_prime_UTR	Exon 7 of 7	NP_001132989.1	O75569-2
	PRKRA	NM_001139518.1		c.*200G>A		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.*200G>A		3_prime_UTR	Exon 8 of 8	ENSP00000318176.4	O75569-1
	PRKRA	ENST00000914393.1		c.*200G>A		3_prime_UTR	Exon 8 of 8	ENSP00000584452.1
	PRKRA	ENST00000677981.1		c.*200G>A		3_prime_UTR	Exon 6 of 6	ENSP00000503536.1	A0A7I2V3J2

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2954 AN: 151750 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0284

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0204 AC: 10500 AN: 513598 Hom.: 0 Cov.: 6 AF XY: 0.0204 AC XY: 5506 AN XY: 270308

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

African (AFR) AF: 0.0197 AC: 256 AN: 12986

American (AMR) AF: 0.00851 AC: 191 AN: 22436

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 475 AN: 14258

East Asian (EAS) AF: 0.00807 AC: 245 AN: 30370

South Asian (SAS) AF: 0.0118 AC: 555 AN: 47226

European-Finnish (FIN) AF: 0.0290 AC: 817 AN: 28174

Middle Eastern (MID) AF: 0.0260 AC: 53 AN: 2038

European-Non Finnish (NFE) AF: 0.0225 AC: 7395 AN: 328466

Other (OTH) AF: 0.0186 AC: 513 AN: 27644

⚠️ 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: 0.0195 AC: 2954 AN: 151868 Hom.: 0 Cov.: 35 AF XY: 0.0193 AC XY: 1430 AN XY: 74248

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

African (AFR) AF: 0.0193 AC: 800 AN: 41422

American (AMR) AF: 0.00622 AC: 95 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0284 AC: 98 AN: 3450

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5168

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4810

European-Finnish (FIN) AF: 0.0296 AC: 313 AN: 10568

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0216 AC: 1463 AN: 67858

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

⚠️ 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: 0.0220 Hom.: 0

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dystonia 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		4.3
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: rs141995027; hg19: chr2-179296624;