rs2304844

Positions:

• chr17-80110708-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.1438-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,610,108 control chromosomes in the GnomAD database, including 405,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.66 (33489 hom., cov: 33)
  • Exomes 𝑓: 0.71 (372161 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.190

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: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-80110708-G-C is Benign according to our data. Variant chr17-80110708-G-C is described in ClinVar as [Benign]. Clinvar id is 92464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80110708-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1438-19G>C		intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1438-19G>C		intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99623 AN: 151992 Hom.: 33476 Cov.: 33

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.667

GnomAD3 exomes AF: 0.670 AC: 167242 AN: 249778 Hom.: 57623 AF XY: 0.684 AC XY: 92524 AN XY: 135250

Gnomad AFR exome AF: 0.532

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.528

Gnomad SAS exome AF: 0.675

Gnomad FIN exome AF: 0.764

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.721

GnomAD4 exome AF: 0.712 AC: 1037728 AN: 1457998 Hom.: 372161 Cov.: 33 AF XY: 0.713 AC XY: 517085 AN XY: 725436

Gnomad4 AFR exome AF: 0.534

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.673

Gnomad4 FIN exome AF: 0.766

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.709

GnomAD4 genome AF: 0.655 AC: 99667 AN: 152110 Hom.: 33489 Cov.: 33 AF XY: 0.653 AC XY: 48561 AN XY: 74356

Gnomad4 AFR AF: 0.532

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.666

Alfa AF: 0.711 Hom.: 7129

Bravo AF: 0.636

Asia WGS AF: 0.587 AC: 2046 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, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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, 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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.35
BranchPoint Hunter		3.0

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: rs2304844; hg19: chr17-78084507;