2-218827579-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017431.4(PRKAG3):c.871G>T(p.Asp291Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4	c.871G>T	p.Asp291Tyr	missense_variant	8/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7	c.871G>T	p.Asp291Tyr	missense_variant	8/14	1	NM_017431.4	P1
PRKAG3	ENST00000529249.5	c.871G>T	p.Asp291Tyr	missense_variant	8/13	1		P1
PRKAG3	ENST00000490971.1	n.1029G>T		non_coding_transcript_exon_variant	7/9	2
PRKAG3	ENST00000470307.6	c.825G>T	p.Met275Ile	missense_variant, NMD_transcript_variant	7/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.871G>T (p.D291Y) alteration is located in exon 8 (coding exon 8) of the PRKAG3 gene. This alteration results from a G to T substitution at nucleotide position 871, causing the aspartic acid (D) at amino acid position 291 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.40	T
REVEL	Pathogenic	0.71
Sift4G	Uncertain	0.028	D;D
Polyphen		0.75	P;P
Vest4		0.47
MutPred		0.51		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.96
MPC		0.25
ClinPred		0.88	D
GERP RS		3.7
Varity_R		0.087
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219692302;