chr12-49005079-G-A

Variant names:

• chr12-49005079-G-A
• rs2293445
• NM_002733.5:c.355+41C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002733.5(PRKAG1):​c.355+41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,612,624 control chromosomes in the GnomAD database, including 118,934 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10117 hom., cov: 31)
  • Exomes 𝑓: 0.38 (108817 hom.)
• Consequence: PRKAG1 NM_002733.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.400
• Publications: 22 publications found

Genes affected

PRKAG1 (HGNC:9385): (protein kinase AMP-activated non-catalytic subunit gamma 1) The protein encoded by this gene is a regulatory 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. This subunit is one of the gamma regulatory subunits of AMPK. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ENSG00000288710 (HGNC:):

DDN-AS1 (HGNC:53464): (DDN and PRKAG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG1	NM_002733.5	c.355+41C>T		intron_variant	Intron 6 of 11	ENST00000548065.7	NP_002724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG1	ENST00000548065.7	c.355+41C>T		intron_variant	Intron 6 of 11	1	NM_002733.5	ENSP00000447433.1
ENSG00000288710	ENST00000683988.1	n.*422+41C>T		intron_variant	Intron 10 of 15			ENSP00000506939.1

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54854 AN: 151680 Hom.: 10104 Cov.: 31

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.366 AC: 92097 AN: 251386 AF XY: 0.373

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.436

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.362

GnomAD4 exome AF: 0.383 AC: 559450 AN: 1460826 Hom.: 108817 Cov.: 37 AF XY: 0.384 AC XY: 279100 AN XY: 726842

African (AFR) AF: 0.318 AC: 10643 AN: 33452

American (AMR) AF: 0.265 AC: 11866 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6693 AN: 26132

East Asian (EAS) AF: 0.397 AC: 15767 AN: 39690

South Asian (SAS) AF: 0.427 AC: 36811 AN: 86216

European-Finnish (FIN) AF: 0.413 AC: 22034 AN: 53414

Middle Eastern (MID) AF: 0.271 AC: 1565 AN: 5766

European-Non Finnish (NFE) AF: 0.388 AC: 431269 AN: 1111074

Other (OTH) AF: 0.378 AC: 22802 AN: 60360

GnomAD4 genome AF: 0.362 AC: 54905 AN: 151798 Hom.: 10117 Cov.: 31 AF XY: 0.362 AC XY: 26815 AN XY: 74156

African (AFR) AF: 0.322 AC: 13300 AN: 41356

American (AMR) AF: 0.311 AC: 4751 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 845 AN: 3468

East Asian (EAS) AF: 0.425 AC: 2198 AN: 5168

South Asian (SAS) AF: 0.450 AC: 2163 AN: 4812

European-Finnish (FIN) AF: 0.413 AC: 4353 AN: 10536

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26189 AN: 67900

Other (OTH) AF: 0.336 AC: 705 AN: 2100

Alfa AF: 0.368 Hom.: 17326

Bravo AF: 0.346

Asia WGS AF: 0.426 AC: 1481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.54
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs2293445; hg19: chr12-49398862; COSMIC: COSV60292836; COSMIC: COSV60292836;