chr12-49005789-A-G

Variant names:

• chr12-49005789-A-G
• NM_002733.5:c.122T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002733.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG1	NM_002733.5	MANE Select	c.122T>C	p.Leu41Pro	missense	Exon 3 of 12	NP_002724.1	P54619-1
	PRKAG1	NM_001206709.2		c.122T>C	p.Leu41Pro	missense	Exon 3 of 12	NP_001193638.1	P54619-3
	PRKAG1	NM_001206710.2		c.26T>C	p.Leu9Pro	missense	Exon 3 of 12	NP_001193639.1	P54619-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG1	ENST00000548065.7	TSL:1 MANE Select	c.122T>C	p.Leu41Pro	missense	Exon 3 of 12	ENSP00000447433.1	P54619-1
	ENSG00000288710	ENST00000683988.1		n.*189T>C		non_coding_transcript_exon	Exon 7 of 16	ENSP00000506939.1	A0A804HI77
	ENSG00000288710	ENST00000683988.1		n.*189T>C		3_prime_UTR	Exon 7 of 16	ENSP00000506939.1	A0A804HI77

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.75		Gain of catalytic residue at H36 (P = 0.0014)
MVP		1.0
MPC		1.0
ClinPred		0.99	D
GERP RS		5.9
PromoterAI		-0.016	Neutral
Varity_R		0.96
gMVP		0.90
Mutation Taster		=207/93	polymorphism

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

hg19: chr12-49399572;