dbSNP rs2304837: GAA:c.1888+21G>A (chr17-80112732-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000152.5(GAA):c.1888+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,598,582 control chromosomes in the GnomAD database, including 2,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 308 hom., cov: 33)

Exomes 𝑓: 0.046 ( 2665 hom. )

Consequence

GAA
NM_000152.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.474

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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 17-80112732-G-A is Benign according to our data. Variant chr17-80112732-G-A is described in ClinVar as Benign. ClinVar VariationId is 255357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
GAA	NM_000152.5	MANE Select	c.1888+21G>A	intron	N/A	NP_000143.2	P10253
GAA	NM_001079803.3		c.1888+21G>A	intron	N/A	NP_001073271.1	P10253
GAA	NM_001079804.3		c.1888+21G>A	intron	N/A	NP_001073272.1	P10253

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GAA	ENST00000302262.8	TSL:1 MANE Select	c.1888+21G>A	intron	N/A	ENSP00000305692.3	P10253
GAA	ENST00000390015.7	TSL:1	c.1888+21G>A	intron	N/A	ENSP00000374665.3	P10253
GAA	ENST00000933406.1		c.1903+21G>A	intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.0437

AC:

6643

AN:

152178

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0391

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.238

Gnomad SAS

AF:

0.0687

Gnomad FIN

AF:

0.0652

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0395

Gnomad OTH

AF:

0.0402

GnomAD2 exomes

AF:

0.0577

AC:

12313

AN:

213296

AF XY:

0.0577

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.0268

Gnomad ASJ exome

AF:

0.0415

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.0651

Gnomad NFE exome

AF:

0.0401

Gnomad OTH exome

AF:

0.0591

GnomAD4 exome

AF:

0.0458

AC:

66311

AN:

1446286

Hom.:

2665

Cov.:

AF XY:

0.0465

AC XY:

33394

AN XY:

718268

show subpopulations

African (AFR)

AF:

0.0196

AC:

651

AN:

33248

American (AMR)

AF:

0.0276

AC:

1169

AN:

42380

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

1101

AN:

25772

East Asian (EAS)

AF:

0.258

AC:

10054

AN:

39004

South Asian (SAS)

AF:

0.0618

AC:

5207

AN:

84190

European-Finnish (FIN)

AF:

0.0679

AC:

3448

AN:

50800

Middle Eastern (MID)

AF:

0.0245

AC:

140

AN:

5712

European-Non Finnish (NFE)

AF:

0.0375

AC:

41405

AN:

1105404

Other (OTH)

AF:

0.0525

AC:

3136

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

3782

7565

11347

15130

18912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1672

3344

5016

6688

8360

<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:

0.0437

AC:

6657

AN:

152296

Hom.:

308

Cov.:

AF XY:

0.0455

AC XY:

3386

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0203

AC:

844

AN:

41570

American (AMR)

AF:

0.0389

AC:

596

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0409

AC:

142

AN:

3468

East Asian (EAS)

AF:

0.239

AC:

1235

AN:

5168

South Asian (SAS)

AF:

0.0689

AC:

333

AN:

4830

European-Finnish (FIN)

AF:

0.0652

AC:

693

AN:

10628

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0395

AC:

2683

AN:

68000

Other (OTH)

AF:

0.0430

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

323

646

970

1293

1616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0286

Hom.:

Bravo

AF:

0.0399

Asia WGS

AF:

0.155

AC:

541

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Glycogen storage disease, type II (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.3

(source)

DANN

Benign

0.86

PhyloP100

0.47

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over