1-56703967-C-T

Variant names:

• chr1-56703967-C-T
• rs112086177
• NM_006252.4:c.789-4C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_006252.4(PRKAA2):​c.789-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,593,470 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: PRKAA2 NM_006252.4 splice_region, intron
• Scores: Splicing: ADA: 0.003431
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.466
• Publications: 0 publications found

Genes affected

PRKAA2 (HGNC:9377): (protein kinase AMP-activated catalytic subunit alpha 2) The protein encoded by this gene is a catalytic 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. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-56703967-C-T is Benign according to our data. Variant chr1-56703967-C-T is described in ClinVar as Benign. ClinVar VariationId is 730280.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 290 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAA2	NM_006252.4	MANE Select	c.789-4C>T		splice_region intron	N/A	NP_006243.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAA2	ENST00000371244.9	TSL:1 MANE Select	c.789-4C>T		splice_region intron	N/A	ENSP00000360290.4	P54646
	PRKAA2	ENST00000860136.1		c.789-4C>T		splice_region intron	N/A	ENSP00000530195.1
	PRKAA2	ENST00000860138.1		c.564-4C>T		splice_region intron	N/A	ENSP00000530197.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00681

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000364 AC: 85 AN: 233792 AF XY: 0.000215

Gnomad AFR exome AF: 0.00473

Gnomad AMR exome AF: 0.000273

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 223 AN: 1441294 Hom.: 1 Cov.: 31 AF XY: 0.000138 AC XY: 99 AN XY: 715440

African (AFR) AF: 0.00501 AC: 165 AN: 32910

American (AMR) AF: 0.000233 AC: 10 AN: 42920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24312

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5664

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102452

Other (OTH) AF: 0.000706 AC: 42 AN: 59526

GnomAD4 genome AF: 0.00191 AC: 290 AN: 152176 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74392

African (AFR) AF: 0.00689 AC: 286 AN: 41506

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00192

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PRKAA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.68
PhyloP100		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0034
dbscSNV1_RF	Benign	0.066
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

Other links and lift over

dbSNP: rs112086177; hg19: chr1-57169640;