rs2252455

Positions:

• chr17-80107908-G-A
• chr17-80107908-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.955+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,594,892 control chromosomes in the GnomAD database, including 403,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33494 hom., cov: 33)
  • Exomes 𝑓: 0.71 (370275 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: -0.701

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=-0.94).
• BP6: Variant 17-80107908-G-A is Benign according to our data. Variant chr17-80107908-G-A is described in ClinVar as [Benign]. Clinvar id is 92491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80107908-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.955+12G>A		intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.955+12G>A		intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99600 AN: 151956 Hom.: 33481 Cov.: 33

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.668

GnomAD3 exomes AF: 0.695 AC: 150388 AN: 216458 Hom.: 52770 AF XY: 0.706 AC XY: 83917 AN XY: 118798

Gnomad AFR exome AF: 0.579

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.785

Gnomad EAS exome AF: 0.559

Gnomad SAS exome AF: 0.689

Gnomad FIN exome AF: 0.776

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.735

GnomAD4 exome AF: 0.714 AC: 1030860 AN: 1442818 Hom.: 370275 Cov.: 40 AF XY: 0.716 AC XY: 512901 AN XY: 716836

Gnomad4 AFR exome AF: 0.535

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.783

Gnomad4 EAS exome AF: 0.567

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.769

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.711

GnomAD4 genome AF: 0.655 AC: 99644 AN: 152074 Hom.: 33494 Cov.: 33 AF XY: 0.653 AC XY: 48558 AN XY: 74348

Gnomad4 AFR AF: 0.531

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.661

Gnomad4 FIN AF: 0.776

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.667

Alfa AF: 0.710 Hom.: 6878

Bravo AF: 0.635

Asia WGS AF: 0.586 AC: 2043 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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)	Sep 04, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 82.703% in ExAC) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.5 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. -
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	- -

Glycogen storage disease, type II Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.64
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: rs2252455; hg19: chr17-78081707; COSMIC: COSV56411424; COSMIC: COSV56411424;