NM_000152.5:c.2446G>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.2446G>A (p.Val816Ile) in gnomAD v2.1.1 is 0.14249 in the African population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92477; 2 star review status) with four submitters classifying the variant as benign, and two as likely 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/CA145772/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.059 ( 537 hom., cov: 33)

Exomes 𝑓: 0.029 ( 1912 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -0.268

Publications

26 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.2446G>A	p.Val816Ile	missense_variant	Exon 17 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.2446G>A	p.Val816Ile	missense_variant	Exon 17 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0593

AC:

9013

AN:

152116

Hom.:

536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.0985

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0497

AC:

12170

AN:

244638

AF XY:

0.0509

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.0940

Gnomad FIN exome

AF:

0.0333

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0320

GnomAD4 exome

AF:

0.0295

AC:

43026

AN:

1459440

Hom.:

1912

Cov.:

AF XY:

0.0320

AC XY:

23214

AN XY:

725992

show subpopulations

African (AFR)

AF:

0.145

AC:

4841

AN:

33462

American (AMR)

AF:

0.0345

AC:

1539

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

517

AN:

26066

East Asian (EAS)

AF:

0.117

AC:

4640

AN:

39674

South Asian (SAS)

AF:

0.136

AC:

11750

AN:

86124

European-Finnish (FIN)

AF:

0.0322

AC:

1673

AN:

51968

Middle Eastern (MID)

AF:

0.0202

AC:

114

AN:

5636

European-Non Finnish (NFE)

AF:

0.0141

AC:

15700

AN:

1111634

Other (OTH)

AF:

0.0373

AC:

2252

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2099

4198

6298

8397

10496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.0593

AC:

9032

AN:

152234

Hom.:

537

Cov.:

AF XY:

0.0610

AC XY:

4539

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.143

AC:

5940

AN:

41522

American (AMR)

AF:

0.0277

AC:

424

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3470

East Asian (EAS)

AF:

0.0983

AC:

508

AN:

5168

South Asian (SAS)

AF:

0.151

AC:

730

AN:

4828

European-Finnish (FIN)

AF:

0.0334

AC:

355

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0137

AC:

934

AN:

68010

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

403

807

1210

1614

2017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0283

Hom.:

196

Bravo

AF:

0.0597

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.141

AC:

622

ESP6500EA

AF:

0.00989

AC:

ExAC

AF:

0.0530

AC:

6427

Asia WGS

AF:

0.140

AC:

485

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:6

Aug 01, 2017

Phosphorus, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

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.2446G>A (p.Val816Ile) in gnomAD v2.1.1 is 0.14249 in the African population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92477; 2 star review status) with four submitters classifying the variant as benign, and two as likely 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Aug 13, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

May 17, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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: 1684505, 25681614, 25526786, 17210890, 8486380, 8094613) -

Cardiovascular phenotype

Benign:1

Jul 24, 2019

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

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.8

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.54

D;D

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.89

L;L

PhyloP100

-0.27

PrimateAI

Benign

0.29

PROVEAN

Benign

0.31

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.16

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0080

B;B

Vest4

0.033

MPC

0.11

ClinPred

0.0097

GERP RS

-9.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.50

Mutation Taster

=96/4

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