Variant 12-119673966-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006253.5(PRKAB1):c.326A>G(p.His109Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PRKAB1
NM_006253.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

Variant links:

Genes affected

PRKAB1 (HGNC:9378): (protein kinase AMP-activated non-catalytic subunit beta 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 may be a positive regulator of AMPK activity. The myristoylation and phosphorylation of this subunit have been shown to affect the enzyme activity and cellular localization of AMPK. This subunit may also serve as an adaptor molecule mediating the association of the AMPK complex. [provided by RefSeq, Jul 2008]

PRKAB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4109754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAB1	NM_006253.5 link	c.326A>G	p.His109Arg	missense_variant, splice_region_variant	3/7	ENST00000229328.10	NP_006244.2	Q9Y478A0A024RBN1
PRKAB1	XM_005253909.2 link	c.326A>G	p.His109Arg	missense_variant, splice_region_variant	4/8		XP_005253966.1	Q9Y478A0A024RBN1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAB1	ENST00000229328.10 link	c.326A>G	p.His109Arg	missense_variant, splice_region_variant	3/7	1	NM_006253.5	ENSP00000229328.5		Q9Y478

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249384

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726418

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 01, 2024

The c.326A>G (p.H109R) alteration is located in exon 3 (coding exon 3) of the PRKAB1 gene. This alteration results from a A to G substitution at nucleotide position 326, causing the histidine (H) at amino acid position 109 to be replaced by an arginine (R). 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

0.15

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;D

Eigen

Benign

0.041

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

.;D

M_CAP

Benign

0.0015

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Benign

0.21

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.015

D;D

Polyphen

0.0030

B;B

Vest4

0.46

MutPred

0.38

Gain of catalytic residue at N111 (P = 0.008);Gain of catalytic residue at N111 (P = 0.008);

MVP

0.76

MPC

0.46

ClinPred

0.41

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.20

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

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