1-56704121-T-C

Variant names:

• chr1-56704121-T-C
• rs41285004
• NM_006252.4:c.939T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_006252.4(PRKAA2):​c.939T>C​(p.Ser313Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,614,184 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (21 hom.)
• Consequence: PRKAA2 NM_006252.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.216
• Publications: 2 publications found

Genes affected

PRKAA2 (HGNC:9377): (protein kinase AMP-activated catalytic subunit alpha 2) The protein encoded by this gene is a catalytic subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-56704121-T-C is Benign according to our data. Variant chr1-56704121-T-C is described in ClinVar as Benign. ClinVar VariationId is 779398.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.216 with no splicing effect.
• BS2: High AC in GnomAd4 at 566 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006252.4. 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
	PRKAA2	NM_006252.4	MANE Select	c.939T>C	p.Ser313Ser	synonymous	Exon 7 of 9	NP_006243.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAA2	ENST00000371244.9	TSL:1 MANE Select	c.939T>C	p.Ser313Ser	synonymous	Exon 7 of 9	ENSP00000360290.4	P54646
	PRKAA2	ENST00000860136.1		c.939T>C	p.Ser313Ser	synonymous	Exon 7 of 9	ENSP00000530195.1
	PRKAA2	ENST00000860138.1		c.714T>C	p.Ser238Ser	synonymous	Exon 6 of 8	ENSP00000530197.1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00330 AC: 830 AN: 251364 AF XY: 0.00295

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00864

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00433 AC: 6333 AN: 1461874 Hom.: 21 Cov.: 31 AF XY: 0.00428 AC XY: 3114 AN XY: 727238

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00239 AC: 107 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86258

European-Finnish (FIN) AF: 0.00874 AC: 467 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00488 AC: 5430 AN: 1111996

Other (OTH) AF: 0.00459 AC: 277 AN: 60396

GnomAD4 genome AF: 0.00372 AC: 566 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74480

African (AFR) AF: 0.000986 AC: 41 AN: 41582

American (AMR) AF: 0.00235 AC: 36 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00453 Hom.: 2

Bravo AF: 0.00307

EpiCase AF: 0.00453

EpiControl AF: 0.00344

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PRKAA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.1
DANN	Benign	0.73
PhyloP100		-0.22
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: rs41285004; hg19: chr1-57169794;