rs2304836

Positions:

• chr17-80113047-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.2040+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,600,158 control chromosomes in the GnomAD database, including 441,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39893 hom., cov: 33)
  • Exomes 𝑓: 0.74 (401353 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.435

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-80113047-A-G is Benign according to our data. Variant chr17-80113047-A-G is described in ClinVar as [Benign]. Clinvar id is 92470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80113047-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2040+20A>G		intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2040+20A>G		intron_variant		1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109674 AN: 151938 Hom.: 39873 Cov.: 33

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.710

GnomAD3 exomes AF: 0.719 AC: 161054 AN: 223990 Hom.: 59061 AF XY: 0.735 AC XY: 90295 AN XY: 122924

Gnomad AFR exome AF: 0.692

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.814

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.743 AC: 1075930 AN: 1448102 Hom.: 401353 Cov.: 51 AF XY: 0.746 AC XY: 536977 AN XY: 719542

Gnomad4 AFR exome AF: 0.702

Gnomad4 AMR exome AF: 0.526

Gnomad4 ASJ exome AF: 0.802

Gnomad4 EAS exome AF: 0.676

Gnomad4 SAS exome AF: 0.809

Gnomad4 FIN exome AF: 0.796

Gnomad4 NFE exome AF: 0.746

Gnomad4 OTH exome AF: 0.749

GnomAD4 genome AF: 0.722 AC: 109737 AN: 152056 Hom.: 39893 Cov.: 33 AF XY: 0.720 AC XY: 53544 AN XY: 74318

Gnomad4 AFR AF: 0.697

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.790

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.811

Gnomad4 FIN AF: 0.808

Gnomad4 NFE AF: 0.751

Gnomad4 OTH AF: 0.710

Alfa AF: 0.746 Hom.: 42613

Bravo AF: 0.704

Asia WGS AF: 0.728 AC: 2535 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 09, 2019	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25626711) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2304836; hg19: chr17-78086846;