17-80113047-A-G

Variant names:

• chr17-80113047-A-G
• rs2304836
• NM_000152.5:c.2040+20A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.2040+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,600,158 control chromosomes in the GnomAD database, including 441,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39893 hom., cov: 33)
  • Exomes 𝑓: 0.74 (401353 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.435
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-80113047-A-G is Benign according to our data. Variant chr17-80113047-A-G is described in ClinVar as Benign. ClinVar VariationId is 92470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.789 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2040+20A>G		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2040+20A>G		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2040+20A>G		intron	N/A	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2040+20A>G		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2040+20A>G		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2055+20A>G		intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109674 AN: 151938 Hom.: 39873 Cov.: 33

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.710

GnomAD2 exomes AF: 0.719 AC: 161054 AN: 223990 AF XY: 0.735

Gnomad AFR exome AF: 0.692

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.743 AC: 1075930 AN: 1448102 Hom.: 401353 Cov.: 51 AF XY: 0.746 AC XY: 536977 AN XY: 719542

African (AFR) AF: 0.702 AC: 23368 AN: 33308

American (AMR) AF: 0.526 AC: 22644 AN: 43014

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20755 AN: 25872

East Asian (EAS) AF: 0.676 AC: 26589 AN: 39304

South Asian (SAS) AF: 0.809 AC: 68429 AN: 84618

European-Finnish (FIN) AF: 0.796 AC: 39280 AN: 49332

Middle Eastern (MID) AF: 0.822 AC: 4697 AN: 5716

European-Non Finnish (NFE) AF: 0.746 AC: 825340 AN: 1107084

Other (OTH) AF: 0.749 AC: 44828 AN: 59854

GnomAD4 genome AF: 0.722 AC: 109737 AN: 152056 Hom.: 39893 Cov.: 33 AF XY: 0.720 AC XY: 53544 AN XY: 74318

African (AFR) AF: 0.697 AC: 28890 AN: 41470

American (AMR) AF: 0.588 AC: 8980 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 2740 AN: 3470

East Asian (EAS) AF: 0.636 AC: 3274 AN: 5150

South Asian (SAS) AF: 0.811 AC: 3914 AN: 4828

European-Finnish (FIN) AF: 0.808 AC: 8565 AN: 10594

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.751 AC: 51031 AN: 67956

Other (OTH) AF: 0.710 AC: 1499 AN: 2112

Alfa AF: 0.741 Hom.: 61589

Bravo AF: 0.704

Asia WGS AF: 0.728 AC: 2535 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type II (5)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.28
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304836; hg19: chr17-78086846;