NM_000152.5:c.2553G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.2553G>A (p.Gly851=) in gnomAD v2.1.1 is 0.63818 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.70216) and European Finnish (0.64436) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92481, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145775/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.58 ( 26128 hom., cov: 32)

Exomes 𝑓: 0.61 ( 275912 hom. )

Consequence

GAA
NM_000152.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:14

Conservation

PhyloP100: -0.607

Publications

30 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

glycogen storage disease II
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
glycogen storage disease due to acid maltase deficiency, infantile onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
glycogen storage disease due to acid maltase deficiency, late-onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.2553G>A	p.Gly851Gly	synonymous_variant	Exon 18 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.2553G>A	p.Gly851Gly	synonymous_variant	Exon 18 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes

AF:

0.580

AC:

88064

AN:

151918

Hom.:

26128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.531

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.696

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.656

Gnomad MID

AF:

0.769

Gnomad NFE

AF:

0.635

Gnomad OTH

AF:

0.601

GnomAD2 exomes

AF:

0.572

AC:

141807

AN:

248116

AF XY:

0.584

show subpopulations

Gnomad AFR exome

AF:

0.533

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.703

Gnomad EAS exome

AF:

0.277

Gnomad FIN exome

AF:

0.647

Gnomad NFE exome

AF:

0.640

Gnomad OTH exome

AF:

0.619

GnomAD4 exome

AF:

0.611

AC:

890500

AN:

1457544

Hom.:

275912

Cov.:

AF XY:

0.612

AC XY:

443382

AN XY:

724652

show subpopulations

African (AFR)

AF:

0.535

AC:

17885

AN:

33414

American (AMR)

AF:

0.441

AC:

19562

AN:

44352

Ashkenazi Jewish (ASJ)

AF:

0.702

AC:

18172

AN:

25898

East Asian (EAS)

AF:

0.278

AC:

11005

AN:

39620

South Asian (SAS)

AF:

0.575

AC:

49310

AN:

85798

European-Finnish (FIN)

AF:

0.644

AC:

34025

AN:

52852

Middle Eastern (MID)

AF:

0.761

AC:

4371

AN:

5740

European-Non Finnish (NFE)

AF:

0.630

AC:

699375

AN:

1109702

Other (OTH)

AF:

0.612

AC:

36795

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18692

37385

56077

74770

93462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18452

36904

55356

73808

92260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.579

AC:

88085

AN:

152036

Hom.:

26128

Cov.:

AF XY:

0.576

AC XY:

42822

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.530

AC:

22012

AN:

41498

American (AMR)

AF:

0.493

AC:

7537

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.696

AC:

2415

AN:

3468

East Asian (EAS)

AF:

0.276

AC:

1417

AN:

5134

South Asian (SAS)

AF:

0.557

AC:

2680

AN:

4814

European-Finnish (FIN)

AF:

0.656

AC:

6947

AN:

10588

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.636

AC:

43173

AN:

67932

Other (OTH)

AF:

0.598

AC:

1262

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1873

3747

5620

7494

9367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.603

Hom.:

10147

Bravo

AF:

0.567

Asia WGS

AF:

0.400

AC:

1396

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

Nov 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The highest continental population minor allele frequency for c.2553G>A (p.Gly851=) in gnomAD v2.1.1 is 0.63818 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.70216) and European Finnish (0.64436) populations. These allele frequencies are higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92481, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 70.344% in gnomAD_ExomesFounderPop) 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.6 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. -

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23418865) -

not specified

Benign:4

Sep 04, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 22, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.0

(source)

DANN

Benign

0.42

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over