12-49003203-G-C

Variant names:

• chr12-49003203-G-C
• rs899020647
• NM_002733.5:c.829C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM2 BP4_Moderate BS2

The NM_002733.5(PRKAG1):​c.829C>G​(p.Leu277Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRKAG1 NM_002733.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity AAKG1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26263255).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG1	NM_002733.5	c.829C>G	p.Leu277Val	missense_variant	Exon 11 of 12	ENST00000548065.7	NP_002724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG1	ENST00000548065.7	c.829C>G	p.Leu277Val	missense_variant	Exon 11 of 12	1	NM_002733.5	ENSP00000447433.1
PRKAG1	ENST00000548362.5	c.124C>G	p.Leu42Val	missense_variant	Exon 2 of 4	3		ENSP00000446987.1
ENSG00000288710	ENST00000683988.1	n.*896C>G		non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000506939.1
ENSG00000288710	ENST00000683988.1	n.*896C>G		3_prime_UTR_variant	Exon 15 of 16			ENSP00000506939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.856C>G (p.L286V) alteration is located in exon 11 (coding exon 11) of the PRKAG1 gene. This alteration results from a C to G substitution at nucleotide position 856, causing the leucine (L) at amino acid position 286 to be replaced by a valine (V). 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	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.26	T;.;.;T;.;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.031
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.14	.;.;.;N;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.090	N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.41	T;T;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;.
Polyphen		0.0	.;.;.;B;.;.;.
Vest4		0.28, 0.30, 0.29, 0.28
MutPred		0.38		.;.;.;Gain of catalytic residue at Y272 (P = 0.0044);.;.;.;
MVP		0.89
MPC		0.52
ClinPred		0.52	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs899020647; hg19: chr12-49396986;