rs6436094

Variant names:

• chr2-218822874-A-G
• rs6436094
• ENST00000439262.7:c.*319T>C

Variant summary

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

The ENST00000439262.7(PRKAG3):​c.*319T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 984,546 control chromosomes in the GnomAD database, including 52,504 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 0.43 (19206 hom., cov: 32)
  • Exomes 𝑓: 0.27 (33298 hom.)
• Consequence: PRKAG3 ENST00000439262.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 23 publications found

Genes affected

PRKAG3 (HGNC:9387): (protein kinase AMP-activated non-catalytic subunit gamma 3) 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. It is dominantly expressed in skeletal muscle. Studies of the pig counterpart suggest that this subunit may play a key role in the regulation of energy metabolism in skeletal muscle. [provided by RefSeq, Jul 2008]

MIR9500 (HGNC:50841): (microRNA 9500) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4	c.*319T>C		3_prime_UTR_variant	Exon 14 of 14		NP_059127.2
MIR9500	NR_128707.1	n.-216A>G		upstream_gene_variant
MIR9500	unassigned_transcript_551	n.-218A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG3	ENST00000439262.7	c.*319T>C		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000397133.3
PRKAG3	ENST00000529249.6	c.*888T>C		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000436068.1
MIR9500	ENST00000635985.1	n.-216A>G		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64988 AN: 152022 Hom.: 19146 Cov.: 32

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.267 AC: 221931 AN: 832406 Hom.: 33298 Cov.: 29 AF XY: 0.266 AC XY: 102317 AN XY: 384458

African (AFR) AF: 0.891 AC: 14057 AN: 15784

American (AMR) AF: 0.301 AC: 296 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 2141 AN: 5144

East Asian (EAS) AF: 0.543 AC: 1968 AN: 3624

South Asian (SAS) AF: 0.280 AC: 4603 AN: 16446

European-Finnish (FIN) AF: 0.150 AC: 43 AN: 286

Middle Eastern (MID) AF: 0.372 AC: 603 AN: 1620

European-Non Finnish (NFE) AF: 0.249 AC: 189769 AN: 761238

Other (OTH) AF: 0.310 AC: 8451 AN: 27282

GnomAD4 genome AF: 0.428 AC: 65102 AN: 152140 Hom.: 19206 Cov.: 32 AF XY: 0.421 AC XY: 31337 AN XY: 74386

African (AFR) AF: 0.840 AC: 34841 AN: 41478

American (AMR) AF: 0.328 AC: 5014 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1492 AN: 3472

East Asian (EAS) AF: 0.505 AC: 2612 AN: 5174

South Asian (SAS) AF: 0.276 AC: 1333 AN: 4824

European-Finnish (FIN) AF: 0.168 AC: 1786 AN: 10610

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16891 AN: 67988

Other (OTH) AF: 0.393 AC: 830 AN: 2114

Alfa AF: 0.284 Hom.: 7406

Bravo AF: 0.459

Asia WGS AF: 0.425 AC: 1477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.88
DANN	Benign	0.57
PhyloP100		-0.49
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: rs6436094; hg19: chr2-219687597;