chr12-49005805-G-A

Variant names:

• chr12-49005805-G-A
• rs755400968
• NM_002733.5:c.106C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_002733.5(PRKAG1):​c.106C>T​(p.His36Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PRKAG1 NM_002733.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.95
• 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• BS2: High AC in GnomAdExome4 at 16 AD gene.

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.106C>T	p.His36Tyr	missense	Exon 3 of 12	NP_002724.1	P54619-1
	PRKAG1	NM_001206709.2		c.106C>T	p.His36Tyr	missense	Exon 3 of 12	NP_001193638.1	P54619-3
	PRKAG1	NM_001206710.2		c.10C>T	p.His4Tyr	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.106C>T	p.His36Tyr	missense	Exon 3 of 12	ENSP00000447433.1	P54619-1
	ENSG00000288710	ENST00000683988.1		n.*173C>T		non_coding_transcript_exon	Exon 7 of 16	ENSP00000506939.1	A0A804HI77
	ENSG00000288710	ENST00000683988.1		n.*173C>T		3_prime_UTR	Exon 7 of 16	ENSP00000506939.1	A0A804HI77

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250886 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461570 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111850

Other (OTH) AF: 0.000132 AC: 8 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

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	0.70
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.6	L
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.80	P
Vest4		0.81
MutPred		0.55		Gain of catalytic residue at R37 (P = 0.0135)
MVP		0.97
MPC		0.37
ClinPred		0.88	D
GERP RS		5.9
PromoterAI		-0.043	Neutral
Varity_R		0.90
gMVP		0.73
Mutation Taster		=222/78	polymorphism

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

Other links and lift over

dbSNP: rs755400968; hg19: chr12-49399588; COSMIC: COSV60294791; COSMIC: COSV60294791;