17-80104844-C-A

Variant names:

• chr17-80104844-C-A
• rs146615896
• NM_000152.5:c.258C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1 BP7 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.258C>A (p.Pro86=) variant in GAA is a synonymous variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.00509 (382/75054 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for BS1 (>0.005), meeting this criterion (BS1). The variant is not predicted to impact splicing; the nucleotide is not conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 282138). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7. (Classification approved by the ClinGen Lysosomal Diseases VCEP on December 5, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814829/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:8
• Conservation: PhyloP100: -0.367
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.258C>A	p.Pro86Pro	synonymous	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.258C>A	p.Pro86Pro	synonymous	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.258C>A	p.Pro86Pro	synonymous	Exon 2 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.258C>A	p.Pro86Pro	synonymous	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.258C>A	p.Pro86Pro	synonymous	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.258C>A	p.Pro86Pro	synonymous	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152238 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000411 AC: 102 AN: 247930 AF XY: 0.000341

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1460538 Hom.: 0 Cov.: 31 AF XY: 0.000150 AC XY: 109 AN XY: 726588

African (AFR) AF: 0.00460 AC: 154 AN: 33466

American (AMR) AF: 0.000336 AC: 15 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52348

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111894

Other (OTH) AF: 0.000215 AC: 13 AN: 60374

GnomAD4 genome AF: 0.00159 AC: 243 AN: 152356 Hom.: 3 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74498

African (AFR) AF: 0.00548 AC: 228 AN: 41588

American (AMR) AF: 0.000588 AC: 9 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000686 Hom.: 1

Bravo AF: 0.00181

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.8
DANN	Benign	0.80
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism

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: rs146615896; hg19: chr17-78078643;