rs776948121

Variant names:

• chr17-80112928-C-A
• rs776948121
• NM_000152.5:c.1941C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80112928-C-A
• chr17-80112928-C-G
• chr17-80112928-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1941C>A (p.Cys647Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individual with Pompe disease. However, there is a ClinVar entry for this variant (Variation ID: 663894). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369921/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: -1.20
• Publications: 12 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1941C>A	p.Cys647*	stop_gained	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1941C>A	p.Cys647*	stop_gained	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1941C>A	p.Cys647*	stop_gained	Exon 14 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.1941C>A	p.Cys647*	stop_gained	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1941C>A	p.Cys647*	stop_gained	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1956C>A	p.Cys652*	stop_gained	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458150 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725018

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110830

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Glycogen storage disease, type II (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.53	D
PhyloP100		-1.2
Vest4		0.95
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs776948121; hg19: chr17-78086727;