17-80104910-T-C

Variant names:

• chr17-80104910-T-C
• rs1800300
• NM_000152.5:c.324T>C

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.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 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/CA145781/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.72 (39941 hom., cov: 34)
  • Exomes 𝑓: 0.74 (404400 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:19
• Conservation: PhyloP100: 2.04
• Publications: 37 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 -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.324T>C	p.Cys108Cys	synonymous	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.324T>C	p.Cys108Cys	synonymous	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.324T>C	p.Cys108Cys	synonymous	Exon 2 of 20	NP_001073272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.324T>C	p.Cys108Cys	synonymous	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.324T>C	p.Cys108Cys	synonymous	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.324T>C	p.Cys108Cys	synonymous	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109760 AN: 152070 Hom.: 39921 Cov.: 34

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.708

GnomAD2 exomes AF: 0.723 AC: 178297 AN: 246688 AF XY: 0.738

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.628

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.756

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.743 AC: 1084167 AN: 1459628 Hom.: 404400 Cov.: 80 AF XY: 0.746 AC XY: 541839 AN XY: 726082

African (AFR) AF: 0.701 AC: 23465 AN: 33460

American (AMR) AF: 0.526 AC: 23417 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20960 AN: 26120

East Asian (EAS) AF: 0.683 AC: 27075 AN: 39640

South Asian (SAS) AF: 0.813 AC: 70031 AN: 86184

European-Finnish (FIN) AF: 0.799 AC: 41532 AN: 52006

Middle Eastern (MID) AF: 0.819 AC: 4725 AN: 5766

European-Non Finnish (NFE) AF: 0.745 AC: 827766 AN: 1111558

Other (OTH) AF: 0.749 AC: 45196 AN: 60336

GnomAD4 genome AF: 0.722 AC: 109824 AN: 152188 Hom.: 39941 Cov.: 34 AF XY: 0.721 AC XY: 53629 AN XY: 74414

African (AFR) AF: 0.696 AC: 28896 AN: 41524

American (AMR) AF: 0.588 AC: 9000 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 2737 AN: 3472

East Asian (EAS) AF: 0.641 AC: 3310 AN: 5164

South Asian (SAS) AF: 0.814 AC: 3931 AN: 4830

European-Finnish (FIN) AF: 0.809 AC: 8587 AN: 10614

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

European-Non Finnish (NFE) AF: 0.751 AC: 51028 AN: 67980

Other (OTH) AF: 0.708 AC: 1494 AN: 2110

Alfa AF: 0.743 Hom.: 73955

Bravo AF: 0.704

Asia WGS AF: 0.732 AC: 2546 AN: 3478

EpiCase AF: 0.753

EpiControl AF: 0.756

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	Glycogen storage disease, type II (7)
-	-	6	not specified (6)
-	1	4	not provided (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.0
DANN	Benign	0.60
PhyloP100		2.0
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: rs1800300; hg19: chr17-78078709; COSMIC: COSV56406822; COSMIC: COSV56406822;