rs2304840

chr17-80112112-G-A

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.1754+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0627 in 1,608,178 control chromosomes in the GnomAD database, including 3,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (314 hom., cov: 34)
  • Exomes 𝑓: 0.063 (3023 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.945

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-80112112-G-A is Benign according to our data. Variant chr17-80112112-G-A is described in ClinVar as [Benign]. Clinvar id is 92468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80112112-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1754+12G>A		intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1754+12G>A		intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0627 AC: 9542 AN: 152156 Hom.: 312 Cov.: 34

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0421

Gnomad SAS AF: 0.0615

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0535

GnomAD3 exomes AF: 0.0560 AC: 14040 AN: 250846 Hom.: 450 AF XY: 0.0568 AC XY: 7714 AN XY: 135700

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.0375

Gnomad SAS exome AF: 0.0651

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0626 AC: 91209 AN: 1455904 Hom.: 3023 Cov.: 29 AF XY: 0.0624 AC XY: 45213 AN XY: 724644

Gnomad4 AFR exome AF: 0.0775

Gnomad4 AMR exome AF: 0.0264

Gnomad4 ASJ exome AF: 0.0397

Gnomad4 EAS exome AF: 0.0431

Gnomad4 SAS exome AF: 0.0633

Gnomad4 FIN exome AF: 0.0546

Gnomad4 NFE exome AF: 0.0657

Gnomad4 OTH exome AF: 0.0586

GnomAD4 genome AF: 0.0628 AC: 9557 AN: 152274 Hom.: 314 Cov.: 34 AF XY: 0.0609 AC XY: 4531 AN XY: 74454

Gnomad4 AFR AF: 0.0764

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.0422

Gnomad4 SAS AF: 0.0626

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0638

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0605 Hom.: 65

Bravo AF: 0.0642

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2012	- -

Glycogen storage disease, type II Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.2
Dann	Benign	0.36

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: rs2304840; hg19: chr17-78085911;