12-49005789-A-G

Position:

• chr12-49005789-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002733.5(PRKAG1):​c.122T>C​(p.Leu41Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG1 NM_002733.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG1	NM_002733.5	c.122T>C	p.Leu41Pro	missense_variant	3/12	ENST00000548065.7	NP_002724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG1	ENST00000548065.7	c.122T>C	p.Leu41Pro	missense_variant	3/12	1	NM_002733.5	ENSP00000447433.1
ENSG00000288710	ENST00000683988.1	n.*189T>C		non_coding_transcript_exon_variant	7/16			ENSP00000506939.1
ENSG00000288710	ENST00000683988.1	n.*189T>C		3_prime_UTR_variant	7/16			ENSP00000506939.1

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

Nov 03, 2023

The c.122T>C (p.L41P) alteration is located in exon 3 (coding exon 3) of the PRKAG1 gene. This alteration results from a T to C substitution at nucleotide position 122, causing the leucine (L) at amino acid position 41 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D;.;.;T;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;.;.;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.87
MutPred		0.75		Gain of catalytic residue at H36 (P = 0.0014);Gain of catalytic residue at H36 (P = 0.0014);.;.;.;.;.;.;
MVP		1.0
MPC		1.0
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49399572;