chr12-119668380-C-T

Position:

• chr12-119668380-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006253.5(PRKAB1):​c.136C>T​(p.Leu46Phe) 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: 2.44

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17798695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAB1	NM_006253.5	c.136C>T	p.Leu46Phe	missense_variant	1/7	ENST00000229328.10	NP_006244.2
PRKAB1	XM_005253909.2	c.136C>T	p.Leu46Phe	missense_variant	2/8		XP_005253966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAB1	ENST00000229328.10	c.136C>T	p.Leu46Phe	missense_variant	1/7	1	NM_006253.5	ENSP00000229328.5
PRKAB1	ENST00000541640.5	c.136C>T	p.Leu46Phe	missense_variant	2/8	1		ENSP00000441369.1
PRKAB1	ENST00000630317.1	c.136C>T	p.Leu46Phe	missense_variant	1/2	2		ENSP00000486936.1
PRKAB1	ENST00000537400.1	n.136C>T		non_coding_transcript_exon_variant	1/3	3		ENSP00000444816.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Jul 20, 2021

The c.136C>T (p.L46F) alteration is located in exon 1 (coding exon 1) of the PRKAB1 gene. This alteration results from a C to T substitution at nucleotide position 136, causing the leucine (L) at amino acid position 46 to be replaced by a phenylalanine (F). 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	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.
Eigen	Benign	-0.054
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.55	N;N;.
REVEL	Benign	0.19
Sift	Benign	0.030	D;D;.
Sift4G	Benign	0.71	T;T;T
Polyphen		0.58	P;P;.
Vest4		0.14
MutPred		0.18		Gain of glycosylation at S49 (P = 0.1516);Gain of glycosylation at S49 (P = 0.1516);Gain of glycosylation at S49 (P = 0.1516);
MVP		0.83
MPC		0.69
ClinPred		0.85	D
GERP RS		3.1
Varity_R		0.076
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-120106185;