rs2278619

Positions:

• chr17-80109927-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.1327-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,603,478 control chromosomes in the GnomAD database, including 441,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39729 hom., cov: 33)
  • Exomes 𝑓: 0.74 (401490 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.59

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=-0.92).
• BP6: Variant 17-80109927-A-G is Benign according to our data. Variant chr17-80109927-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 92462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80109927-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1327-18A>G		intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1327-18A>G		intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109467 AN: 152052 Hom.: 39711 Cov.: 33

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.702

GnomAD3 exomes AF: 0.720 AC: 179518 AN: 249242 Hom.: 66104 AF XY: 0.736 AC XY: 99352 AN XY: 135072

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.814

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.742 AC: 1076857 AN: 1451308 Hom.: 401490 Cov.: 28 AF XY: 0.745 AC XY: 538611 AN XY: 722628

Gnomad4 AFR exome AF: 0.697

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.805

Gnomad4 EAS exome AF: 0.676

Gnomad4 SAS exome AF: 0.809

Gnomad4 FIN exome AF: 0.798

Gnomad4 NFE exome AF: 0.744

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.720 AC: 109528 AN: 152170 Hom.: 39729 Cov.: 33 AF XY: 0.719 AC XY: 53480 AN XY: 74408

Gnomad4 AFR AF: 0.692

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.793

Gnomad4 EAS AF: 0.637

Gnomad4 SAS AF: 0.811

Gnomad4 FIN AF: 0.810

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.702

Alfa AF: 0.746 Hom.: 7780

Bravo AF: 0.701

Asia WGS AF: 0.727 AC: 2530 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 28, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Glycogen storage disease, type II Benign:4

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	Mendelics	May 28, 2019	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.92
CADD	Benign	0.0080
DANN	Benign	0.30

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: rs2278619; hg19: chr17-78083726; COSMIC: COSV56408726; COSMIC: COSV56408726;