17-80118674-G-C

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 NM_000152.5:c.2668G>C variant in GAA is predicted to result in the missense substitution of valine by leucine at amino acid position 890. The highest population minor allele frequency in gnomAD v2.1.1 is 0.02652 (812/30616 alleles with 13 homozygotes) in the South Asian population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 255361). In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BA1.(Classified approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815831/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 40 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: 0.0280

Publications

2 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	NM_000152.5	MANE Select	c.2668G>C	p.Val890Leu	missense	Exon 19 of 20	NP_000143.2
GAA	NM_001079803.3		c.2668G>C	p.Val890Leu	missense	Exon 20 of 21	NP_001073271.1
GAA	NM_001079804.3		c.2668G>C	p.Val890Leu	missense	Exon 19 of 20	NP_001073272.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	ENST00000302262.8	TSL:1 MANE Select	c.2668G>C	p.Val890Leu	missense	Exon 19 of 20	ENSP00000305692.3
GAA	ENST00000390015.7	TSL:1	c.2668G>C	p.Val890Leu	missense	Exon 20 of 21	ENSP00000374665.3
GAA	ENST00000570803.6	TSL:5	c.2668G>C	p.Val890Leu	missense	Exon 19 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00338

AC:

845

AN:

250280

AF XY:

0.00429

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00168

AC:

2451

AN:

1460462

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

1699

AN XY:

726506

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39698

South Asian (SAS)

AF:

0.0264

AC:

2275

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52022

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111994

Other (OTH)

AF:

0.00229

AC:

138

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

215

431

646

862

1077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.000873

AC:

133

AN:

152306

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0265

AC:

128

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000239

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00364

AC:

442

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (7)

not specified (3)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.5

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.24

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.85

PhyloP100

0.028

PrimateAI

Benign

0.38

PROVEAN

Benign

0.23

REVEL

Benign

0.18

Sift

Benign

0.59

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.053

MutPred

0.42

Gain of catalytic residue at V890 (P = 5e-04)

MVP

0.85

MPC

0.11

ClinPred

0.0019

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.071

gMVP

0.65

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over