12-49003817-C-T

Variant names:

• chr12-49003817-C-T
• NM_002733.5:c.643G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002733.5(PRKAG1):​c.643G>A​(p.Val215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKAG1 NM_002733.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21315283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG1	NM_002733.5	c.643G>A	p.Val215Met	missense_variant	Exon 9 of 12	ENST00000548065.7	NP_002724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG1	ENST00000548065.7	c.643G>A	p.Val215Met	missense_variant	Exon 9 of 12	1	NM_002733.5	ENSP00000447433.1
ENSG00000288710	ENST00000683988.1	n.*710G>A		non_coding_transcript_exon_variant	Exon 13 of 16			ENSP00000506939.1
ENSG00000288710	ENST00000683988.1	n.*710G>A		3_prime_UTR_variant	Exon 13 of 16			ENSP00000506939.1
PRKAG1	ENST00000548362.5	c.-224G>A		upstream_gene_variant		3		ENSP00000446987.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.670G>A (p.V224M) alteration is located in exon 9 (coding exon 9) of the PRKAG1 gene. This alteration results from a G to A substitution at nucleotide position 670, causing the valine (V) at amino acid position 224 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.019	.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.28	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	0.37	D
PROVEAN	Benign	1.2	N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
MutPred		0.52		Gain of catalytic residue at L142 (P = 0);.;
MVP		0.83
ClinPred		0.24	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr12-49397600;