chr17-80104844-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1BP7BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.258C>A (p.Pro86=) variant in GAA is a synonymous variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.00509 (382/75054 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for BS1 (>0.005), meeting this criterion (BS1). The variant is not predicted to impact splicing; the nucleotide is not conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 282138). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7. (Classification approved by the ClinGen Lysosomal Diseases VCEP on December 5, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814829/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

GAA
NM_000152.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:8

Conservation

PhyloP100: -0.367

Publications

5 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: Likely_benign. The variant received -6 ACMG points.

BP4

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

BP7

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

BS1

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.258C>A	p.Pro86Pro	synonymous_variant	Exon 2 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.258C>A	p.Pro86Pro	synonymous_variant	Exon 2 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00552

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000411

AC:

102

AN:

247930

AF XY:

0.000341

show subpopulations

Gnomad AFR exome

AF:

0.00541

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000167

AC:

244

AN:

1460538

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

726588

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33466

American (AMR)

AF:

0.000336

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52348

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000522

AC:

AN:

1111894

Other (OTH)

AF:

0.000215

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00159

AC:

243

AN:

152356

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

112

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00548

AC:

228

AN:

41588

American (AMR)

AF:

0.000588

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000686

Hom.:

Bravo

AF:

0.00181

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GAA: BP4, BP7 -

Feb 03, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GAA c.258C>A (p.Pro86Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of an ESE site. These predictions have yet to be confirmed by functional studies. This variant was found in 69/114570 control chromosomes from ExAC, predominantly observed in the African subpopulation at a frequency of 0.006696 (64/9558). This frequency is about 1.6 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. No homozygotes have been reported in ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. A clinical diagnostic laboratory in ClinVar has classified this variant as benign. Taken together, this variant is classified as Likely Benign. -

Sep 08, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease, type II

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2023

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000152.5: c.258C>A (p.Pro86=) variant in GAA is a synonymous variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.00509 (382/75054 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for BS1 (>0.005), meeting this criterion (BS1). The variant is not predicted to impact splicing; the nucleotide is not conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 282138). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7. (Classification approved by the ClinGen Lysosomal Diseases VCEP on December 5, 2023). -

Mar 07, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 21, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 04, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

-0.54

CADD

Benign

2.8

(source)

DANN

Benign

0.80

PhyloP100

-0.37

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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