Variant 12-49005837-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002733.5(PRKAG1):c.74A>G(p.Asn25Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.9e-7 ( 0 hom. )

Consequence

PRKAG1
NM_002733.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

Variant links:

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]

PRKAG1 links:

ENSG00000288710 (HGNC:):

ENSG00000288710 links:

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ACMG classification

Classification made for transcript

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=0.19447353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG1	NM_002733.5 linkuse as main transcript	c.74A>G	p.Asn25Ser	missense_variant	3/12	ENST00000548065.7	NP_002724.1	P54619-1A0A024R125

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRKAG1	ENST00000548065.7 linkuse as main transcript	c.74A>G	p.Asn25Ser	missense_variant	3/12	1	NM_002733.5	ENSP00000447433.1	P54619-1
ENSG00000288710	ENST00000683988.1 linkuse as main transcript	n.*141A>G		non_coding_transcript_exon_variant	7/16			ENSP00000506939.1	A0A804HI77
ENSG00000288710	ENST00000683988.1 linkuse as main transcript	n.*141A>G		3_prime_UTR_variant	7/16			ENSP00000506939.1	A0A804HI77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245462

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455916

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723854

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.74A>G (p.N25S) alteration is located in exon 3 (coding exon 3) of the PRKAG1 gene. This alteration results from a A to G substitution at nucleotide position 74, causing the asparagine (N) at amino acid position 25 to be replaced by a serine (S). 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

0.059

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.10

.;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.053

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.35

N;N;D

REVEL

Uncertain

0.30

Sift

Benign

0.21

T;T;D

Sift4G

Benign

0.28

T;T;.

Polyphen

0.0

.;B;.

Vest4

0.21

MutPred

0.26

Gain of glycosylation at N25 (P = 0.0155);Gain of glycosylation at N25 (P = 0.0155);.;

MVP

0.86

MPC

0.17

ClinPred

0.32

GERP RS

5.9

Varity_R

0.097

gMVP

0.059

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over