rs1126690

Variant names:

• chr17-80117606-G-A
• rs1126690
• NM_000152.5:c.2338G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80117606-G-A
• chr17-80117606-G-C
• chr17-80117606-G-T

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 highest continental population minor allele frequency for c.2338G>A (p.Val780Ile) in gnomAD v2.1.1 is 0.8129 in the South Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92476; 2 star review status) with six 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/CA145769/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.72 (39719 hom., cov: 32)
  • Exomes 𝑓: 0.74 (404210 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:15
• Conservation: PhyloP100: -1.09
• Publications: 57 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 -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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2338G>A	p.Val780Ile	missense	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2338G>A	p.Val780Ile	missense	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2338G>A	p.Val780Ile	missense	Exon 17 of 20	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.2338G>A	p.Val780Ile	missense	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2338G>A	p.Val780Ile	missense	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2353G>A	p.Val785Ile	missense	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109406 AN: 151932 Hom.: 39700 Cov.: 32

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.717 AC: 178198 AN: 248394 AF XY: 0.733

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.619

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.757

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.742 AC: 1083650 AN: 1460334 Hom.: 404210 Cov.: 57 AF XY: 0.746 AC XY: 541672 AN XY: 726500

African (AFR) AF: 0.699 AC: 23410 AN: 33470

American (AMR) AF: 0.501 AC: 22425 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20960 AN: 26124

East Asian (EAS) AF: 0.672 AC: 26659 AN: 39694

South Asian (SAS) AF: 0.808 AC: 69680 AN: 86254

European-Finnish (FIN) AF: 0.798 AC: 41684 AN: 52238

Middle Eastern (MID) AF: 0.822 AC: 4733 AN: 5758

European-Non Finnish (NFE) AF: 0.746 AC: 828904 AN: 1111714

Other (OTH) AF: 0.749 AC: 45195 AN: 60364

GnomAD4 genome AF: 0.720 AC: 109467 AN: 152050 Hom.: 39719 Cov.: 32 AF XY: 0.719 AC XY: 53428 AN XY: 74328

African (AFR) AF: 0.695 AC: 28821 AN: 41468

American (AMR) AF: 0.578 AC: 8833 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2737 AN: 3468

East Asian (EAS) AF: 0.628 AC: 3237 AN: 5154

South Asian (SAS) AF: 0.809 AC: 3891 AN: 4808

European-Finnish (FIN) AF: 0.809 AC: 8577 AN: 10608

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

European-Non Finnish (NFE) AF: 0.751 AC: 51028 AN: 67950

Other (OTH) AF: 0.712 AC: 1500 AN: 2108

Alfa AF: 0.739 Hom.: 148592

Bravo AF: 0.701

TwinsUK AF: 0.742 AC: 2751

ALSPAC AF: 0.742 AC: 2858

ESP6500AA AF: 0.701 AC: 3087

ESP6500EA AF: 0.750 AC: 6446

ExAC AF: 0.728 AC: 88350

Asia WGS AF: 0.723 AC: 2517 AN: 3478

EpiCase AF: 0.754

EpiControl AF: 0.756

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.2
DANN	Benign	0.65
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.16
Sift	Benign	0.59	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.043
MPC		0.088
ClinPred		0.00059	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1126690; hg19: chr17-78091405; COSMIC: COSV56407159; COSMIC: COSV56407159;