12-49003819-T-C

Variant names:

• chr12-49003819-T-C
• rs199843731
• NM_002733.5:c.641A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002733.5(PRKAG1):​c.641A>G​(p.Tyr214Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: PRKAG1 NM_002733.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24130014).
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG1	NM_002733.5	c.641A>G	p.Tyr214Cys	missense_variant	Exon 9 of 12	ENST00000548065.7	NP_002724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG1	ENST00000548065.7	c.641A>G	p.Tyr214Cys	missense_variant	Exon 9 of 12	1	NM_002733.5	ENSP00000447433.1
ENSG00000288710	ENST00000683988.1	n.*708A>G		non_coding_transcript_exon_variant	Exon 13 of 16			ENSP00000506939.1
ENSG00000288710	ENST00000683988.1	n.*708A>G		3_prime_UTR_variant	Exon 13 of 16			ENSP00000506939.1
PRKAG1	ENST00000548362.5	c.-226A>G		upstream_gene_variant		3		ENSP00000446987.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251390 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135864

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000329 AC: 481 AN: 1461820 Hom.: 0 Cov.: 33 AF XY: 0.000319 AC XY: 232 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668A>G (p.Y223C) alteration is located in exon 9 (coding exon 9) of the PRKAG1 gene. This alteration results from a A to G substitution at nucleotide position 668, causing the tyrosine (Y) at amino acid position 223 to be replaced by a cysteine (C). 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	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.019	.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.23	T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Pathogenic	0.84	D
PROVEAN	Benign	0.55	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.25	T;.
MVP		0.87
ClinPred		0.13	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199843731; hg19: chr12-49397602;