rs2252455

Variant names:

• chr17-80107908-G-A
• rs2252455
• NM_000152.5:c.955+12G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107908-G-A
• chr17-80107908-G-C

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.955+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,594,892 control chromosomes in the GnomAD database, including 403,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33494 hom., cov: 33)
  • Exomes 𝑓: 0.71 (370275 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: -0.701
• Publications: 18 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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=-0.94).
• BP6: Variant 17-80107908-G-A is Benign according to our data. Variant chr17-80107908-G-A is described in ClinVar as Benign. ClinVar VariationId is 92491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.955+12G>A		intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.955+12G>A		intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.955+12G>A		intron	N/A	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.955+12G>A		intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.955+12G>A		intron	N/A	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.955+12G>A		intron	N/A	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99600 AN: 151956 Hom.: 33481 Cov.: 33

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.668

GnomAD2 exomes AF: 0.695 AC: 150388 AN: 216458 AF XY: 0.706

Gnomad AFR exome AF: 0.579

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.785

Gnomad EAS exome AF: 0.559

Gnomad FIN exome AF: 0.776

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.735

GnomAD4 exome AF: 0.714 AC: 1030860 AN: 1442818 Hom.: 370275 Cov.: 40 AF XY: 0.716 AC XY: 512901 AN XY: 716836

African (AFR) AF: 0.535 AC: 17701 AN: 33064

American (AMR) AF: 0.513 AC: 20764 AN: 40514

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 20279 AN: 25898

East Asian (EAS) AF: 0.567 AC: 21927 AN: 38706

South Asian (SAS) AF: 0.677 AC: 57108 AN: 84298

European-Finnish (FIN) AF: 0.769 AC: 38967 AN: 50686

Middle Eastern (MID) AF: 0.802 AC: 3807 AN: 4748

European-Non Finnish (NFE) AF: 0.731 AC: 807882 AN: 1105208

Other (OTH) AF: 0.711 AC: 42425 AN: 59696

GnomAD4 genome AF: 0.655 AC: 99644 AN: 152074 Hom.: 33494 Cov.: 33 AF XY: 0.653 AC XY: 48558 AN XY: 74348

African (AFR) AF: 0.531 AC: 22015 AN: 41470

American (AMR) AF: 0.556 AC: 8505 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2674 AN: 3472

East Asian (EAS) AF: 0.540 AC: 2786 AN: 5164

South Asian (SAS) AF: 0.661 AC: 3187 AN: 4818

European-Finnish (FIN) AF: 0.776 AC: 8220 AN: 10596

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50009 AN: 67952

Other (OTH) AF: 0.667 AC: 1408 AN: 2110

Alfa AF: 0.705 Hom.: 6976

Bravo AF: 0.635

Asia WGS AF: 0.586 AC: 2043 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	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: rs2252455; hg19: chr17-78081707; COSMIC: COSV56411424; COSMIC: COSV56411424;