rs1800309

Variant names:

• chr17-80113242-G-A
• rs1800309
• NM_000152.5:c.2065G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80113242-G-A
• chr17-80113242-G-C
• chr17-80113242-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.2065G>A​(p.Glu689Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,601,260 control chromosomes in the GnomAD database, including 2,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (308 hom., cov: 34)
  • Exomes 𝑓: 0.046 (2661 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts P:1 B:14 O:3
• Conservation: PhyloP100: 2.05
• Publications: 92 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 -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000152.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015834868).
• BP6: Variant 17-80113242-G-A is Benign according to our data. Variant chr17-80113242-G-A is described in ClinVar as Benign|other. ClinVar VariationId is 4030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 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.2065G>A	p.Glu689Lys	missense	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2065G>A	p.Glu689Lys	missense	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2065G>A	p.Glu689Lys	missense	Exon 15 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.2065G>A	p.Glu689Lys	missense	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2065G>A	p.Glu689Lys	missense	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2080G>A	p.Glu694Lys	missense	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6657 AN: 152194 Hom.: 305 Cov.: 34

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0653

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0556 AC: 12525 AN: 225448 AF XY: 0.0556

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.234

Gnomad FIN exome AF: 0.0621

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0573

GnomAD4 exome AF: 0.0457 AC: 66223 AN: 1448948 Hom.: 2661 Cov.: 35 AF XY: 0.0463 AC XY: 33325 AN XY: 719752

African (AFR) AF: 0.0195 AC: 651 AN: 33310

American (AMR) AF: 0.0272 AC: 1175 AN: 43196

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1102 AN: 25806

East Asian (EAS) AF: 0.257 AC: 10060 AN: 39104

South Asian (SAS) AF: 0.0612 AC: 5132 AN: 83920

European-Finnish (FIN) AF: 0.0670 AC: 3425 AN: 51086

Middle Eastern (MID) AF: 0.0247 AC: 142 AN: 5746

European-Non Finnish (NFE) AF: 0.0374 AC: 41410 AN: 1106876

Other (OTH) AF: 0.0522 AC: 3126 AN: 59904

GnomAD4 genome AF: 0.0438 AC: 6671 AN: 152312 Hom.: 308 Cov.: 34 AF XY: 0.0456 AC XY: 3396 AN XY: 74472

African (AFR) AF: 0.0205 AC: 853 AN: 41580

American (AMR) AF: 0.0389 AC: 595 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.238 AC: 1232 AN: 5168

South Asian (SAS) AF: 0.0691 AC: 334 AN: 4832

European-Finnish (FIN) AF: 0.0653 AC: 694 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2691 AN: 68014

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0481 Hom.: 651

Bravo AF: 0.0399

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.0348 AC: 299

ExAC AF: 0.0515 AC: 6210

Asia WGS AF: 0.149 AC: 520 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (8)
-	-	5	not specified (5)
-	-	2	not provided (3)
1	-	-	Acid alpha-glucosidase, allele 4 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.35	T
Sift4G	Benign	0.67	T
Polyphen		0.092	B
Vest4		0.080
MPC		0.14
ClinPred		0.0035	T
GERP RS		1.5
Varity_R		0.086
gMVP		0.53
Mutation Taster		=98/2	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: rs1800309; hg19: chr17-78087041; COSMIC: COSV56407168; COSMIC: COSV56407168;