12-119668361-C-G

Position:

• chr12-119668361-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006253.5(PRKAB1):​c.117C>G​(p.Asp39Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAB1 NM_006253.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.500

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]

ACMG classification

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=0.276523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAB1	NM_006253.5	c.117C>G	p.Asp39Glu	missense_variant	1/7	ENST00000229328.10	NP_006244.2
PRKAB1	XM_005253909.2	c.117C>G	p.Asp39Glu	missense_variant	2/8		XP_005253966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAB1	ENST00000229328.10	c.117C>G	p.Asp39Glu	missense_variant	1/7	1	NM_006253.5	ENSP00000229328.5
PRKAB1	ENST00000541640.5	c.117C>G	p.Asp39Glu	missense_variant	2/8	1		ENSP00000441369.1
PRKAB1	ENST00000630317.1	c.117C>G	p.Asp39Glu	missense_variant	1/2	2		ENSP00000486936.1
PRKAB1	ENST00000537400.1	n.117C>G		non_coding_transcript_exon_variant	1/3	3		ENSP00000444816.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Apr 21, 2022

The c.117C>G (p.D39E) alteration is located in exon 1 (coding exon 1) of the PRKAB1 gene. This alteration results from a C to G substitution at nucleotide position 117, causing the aspartic acid (D) at amino acid position 39 to be replaced by a glutamic acid (E). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.0078	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.76	N;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.31	T;T;D
Polyphen		0.36	B;B;.
Vest4		0.51
MutPred		0.27		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.78
MPC		0.70
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.12
gMVP		0.29

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

Other links and lift over

dbSNP: rs1955356617; hg19: chr12-120106166;