5-40765115-T-C

Position:

• chr5-40765115-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006251.6(PRKAA1):​c.945A>G​(p.Glu315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,614,196 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (56 hom.)
• Consequence: PRKAA1 NM_006251.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.234

Genes affected

PRKAA1 (HGNC:9376): (protein kinase AMP-activated catalytic subunit alpha 1) The protein encoded by this gene belongs to the ser/thr protein kinase family. It is the catalytic subunit of the 5'-prime-AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor conserved in all eukaryotic cells. The kinase activity of AMPK is activated by the stimuli that increase the cellular AMP/ATP ratio. AMPK regulates the activities of a number of key metabolic enzymes through phosphorylation. It protects cells from stresses that cause ATP depletion by switching off ATP-consuming biosynthetic pathways. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

LOC124900968 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-40765115-T-C is Benign according to our data. Variant chr5-40765115-T-C is described in ClinVar as [Benign]. Clinvar id is 725539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.234 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00214 (326/152332) while in subpopulation SAS AF= 0.0184 (89/4828). AF 95% confidence interval is 0.0153. There are 4 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAA1	NM_006251.6	c.945A>G	p.Glu315=	synonymous_variant	7/9	ENST00000397128.7
LOC124900968	XR_007058747.1	n.1451+648T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAA1	ENST00000397128.7	c.945A>G	p.Glu315=	synonymous_variant	7/9	1	NM_006251.6	P1
PRKAA1	ENST00000354209.7	c.990A>G	p.Glu330=	synonymous_variant	8/10	1
PRKAA1	ENST00000505783.5	n.574A>G		non_coding_transcript_exon_variant	4/4	2
PRKAA1	ENST00000506652.5	n.904A>G		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 328 AN: 152214 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00440 AC: 1098 AN: 249534 Hom.: 15 AF XY: 0.00544 AC XY: 736 AN XY: 135374

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00726

GnomAD4 exome AF: 0.00272 AC: 3973 AN: 1461864 Hom.: 56 Cov.: 31 AF XY: 0.00335 AC XY: 2433 AN XY: 727236

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00804

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152332 Hom.: 4 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74494

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00231 Hom.: 1

Bravo AF: 0.00177

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00290

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.0
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs56138995; hg19: chr5-40765217;