rs142626724

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 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/CA198776/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0062 ( 2 hom., cov: 34)
Exomes 𝑓: 0.0084 ( 72 hom. )

Consequence

GAA
NM_000152.5 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel B:14

Conservation

PhyloP100: -0.377
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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
GAANM_000152.5 linkc.852G>A p.Ala284Ala synonymous_variant Exon 4 of 20 ENST00000302262.8 NP_000143.2 P10253

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GAAENST00000302262.8 linkc.852G>A p.Ala284Ala synonymous_variant Exon 4 of 20 1 NM_000152.5 ENSP00000305692.3 P10253

Frequencies

GnomAD3 genomes
AF:
0.00626
AC:
895
AN:
142998
Hom.:
2
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00162
Gnomad AMI
AF:
0.00920
Gnomad AMR
AF:
0.00595
Gnomad ASJ
AF:
0.00927
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00204
Gnomad FIN
AF:
0.00266
Gnomad MID
AF:
0.0199
Gnomad NFE
AF:
0.0100
Gnomad OTH
AF:
0.0106
GnomAD3 exomes
AF:
0.00629
AC:
1563
AN:
248578
Hom.:
5
AF XY:
0.00650
AC XY:
878
AN XY:
135026
show subpopulations
Gnomad AFR exome
AF:
0.00137
Gnomad AMR exome
AF:
0.00452
Gnomad ASJ exome
AF:
0.00602
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00239
Gnomad FIN exome
AF:
0.00269
Gnomad NFE exome
AF:
0.0103
Gnomad OTH exome
AF:
0.00775
GnomAD4 exome
AF:
0.00840
AC:
12263
AN:
1460388
Hom.:
72
Cov.:
34
AF XY:
0.00830
AC XY:
6033
AN XY:
726540
show subpopulations
Gnomad4 AFR exome
AF:
0.00176
Gnomad4 AMR exome
AF:
0.00494
Gnomad4 ASJ exome
AF:
0.00701
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00237
Gnomad4 FIN exome
AF:
0.00308
Gnomad4 NFE exome
AF:
0.00972
Gnomad4 OTH exome
AF:
0.00824
GnomAD4 genome
AF:
0.00624
AC:
893
AN:
143118
Hom.:
2
Cov.:
34
AF XY:
0.00581
AC XY:
404
AN XY:
69592
show subpopulations
Gnomad4 AFR
AF:
0.00161
Gnomad4 AMR
AF:
0.00594
Gnomad4 ASJ
AF:
0.00927
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00204
Gnomad4 FIN
AF:
0.00266
Gnomad4 NFE
AF:
0.0100
Gnomad4 OTH
AF:
0.0105
Alfa
AF:
0.00767
Hom.:
1
Bravo
AF:
0.00629
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0136
EpiControl
AF:
0.0127

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glycogen storage disease, type II Benign:5
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 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. -

Jul 08, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Oct 15, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:4
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 22, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 22, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: GAA c.852G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0063 in 248578 control chromosomes, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.852G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) without strong evidence of causality (Gort_2007, Herzog_2012, Kroos_2008) . These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:4
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 30, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

GAA: BP4, BP7, BS2 -

Cardiovascular phenotype Benign:1
Jun 10, 2021
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
-0.69
CADD
Benign
6.2
DANN
Benign
0.73

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142626724; hg19: chr17-78081515; API