rs2304832

Positions:

• chr17-80117129-G-A
• chr17-80117129-G-C

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.2331+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,609,616 control chromosomes in the GnomAD database, including 463,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49159 hom., cov: 33)
  • Exomes 𝑓: 0.75 (414378 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.215

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=-0.94).
• BP6: Variant 17-80117129-G-A is Benign according to our data. Variant chr17-80117129-G-A is described in ClinVar as [Benign]. Clinvar id is 92474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80117129-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2331+20G>A		intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2331+20G>A		intron_variant		1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120997 AN: 152006 Hom.: 49110 Cov.: 33

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.767

GnomAD3 exomes AF: 0.742 AC: 181849 AN: 245184 Hom.: 69163 AF XY: 0.751 AC XY: 100171 AN XY: 133364

Gnomad AFR exome AF: 0.956

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.619

Gnomad SAS exome AF: 0.813

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.758

Gnomad OTH exome AF: 0.767

GnomAD4 exome AF: 0.752 AC: 1095614 AN: 1457492 Hom.: 414378 Cov.: 40 AF XY: 0.754 AC XY: 546841 AN XY: 725140

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.543

Gnomad4 ASJ exome AF: 0.823

Gnomad4 EAS exome AF: 0.674

Gnomad4 SAS exome AF: 0.808

Gnomad4 FIN exome AF: 0.799

Gnomad4 NFE exome AF: 0.747

Gnomad4 OTH exome AF: 0.769

GnomAD4 genome AF: 0.796 AC: 121097 AN: 152124 Hom.: 49159 Cov.: 33 AF XY: 0.792 AC XY: 58914 AN XY: 74382

Gnomad4 AFR AF: 0.948

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.816

Gnomad4 EAS AF: 0.631

Gnomad4 SAS AF: 0.810

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.767

Alfa AF: 0.782 Hom.: 8684

Bravo AF: 0.788

Asia WGS AF: 0.745 AC: 2594 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Glycogen storage disease, type II Benign:3

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.77
DANN	Benign	0.34

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: rs2304832; hg19: chr17-78090928;