rs2304831

Variant names:

• chr17-80117133-T-C
• rs2304831
• NM_000152.5:c.2331+24T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-80117133-T-C
• chr17-80117133-T-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.2331+24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,608,916 control chromosomes in the GnomAD database, including 17,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1835 hom., cov: 33)
  • Exomes 𝑓: 0.13 (15233 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.32
• Publications: 6 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=-1.02).
• BP6: Variant 17-80117133-T-C is Benign according to our data. Variant chr17-80117133-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 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.2331+24T>C		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2331+24T>C		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2331+24T>C		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.2331+24T>C		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2331+24T>C		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2346+24T>C		intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21741 AN: 152082 Hom.: 1830 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.0935

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.149 AC: 36519 AN: 244470 AF XY: 0.152

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.0970

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.131 AC: 191528 AN: 1456716 Hom.: 15233 Cov.: 34 AF XY: 0.134 AC XY: 97123 AN XY: 724778

African (AFR) AF: 0.168 AC: 5636 AN: 33450

American (AMR) AF: 0.0841 AC: 3757 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2643 AN: 26126

East Asian (EAS) AF: 0.392 AC: 15554 AN: 39656

South Asian (SAS) AF: 0.233 AC: 20048 AN: 86180

European-Finnish (FIN) AF: 0.155 AC: 7685 AN: 49654

Middle Eastern (MID) AF: 0.0610 AC: 345 AN: 5660

European-Non Finnish (NFE) AF: 0.115 AC: 127593 AN: 1111038

Other (OTH) AF: 0.137 AC: 8267 AN: 60290

GnomAD4 genome AF: 0.143 AC: 21781 AN: 152200 Hom.: 1835 Cov.: 33 AF XY: 0.145 AC XY: 10783 AN XY: 74414

African (AFR) AF: 0.170 AC: 7079 AN: 41526

American (AMR) AF: 0.0960 AC: 1468 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0935 AC: 324 AN: 3466

East Asian (EAS) AF: 0.351 AC: 1817 AN: 5170

South Asian (SAS) AF: 0.252 AC: 1212 AN: 4818

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10620

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7823 AN: 67984

Other (OTH) AF: 0.117 AC: 247 AN: 2114

Alfa AF: 0.123 Hom.: 276

Bravo AF: 0.138

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Glycogen storage disease, type II (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.36
PhyloP100		-3.3
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: rs2304831; hg19: chr17-78090932; COSMIC: COSV56406922; COSMIC: COSV56406922;