rs786204561

Variant names:

• chr17-80118359-T-A
• rs786204561
• NM_000152.5:c.2646+2T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80118359-T-A
• chr17-80118359-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4 PM3_Strong PVS1_Moderate PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.2646+2T>A, alters the canonical donor splice site of intron 18. RT-PCR analysis revealed that the variant results in the use of a cryptic splice site in exon 18, deleting the last 21 nucleotides of the exon, corresponding to the loss of 7 amino acids (PMID 11854868). As <10% of the protein in lost, PVS1_Moderate was applied. The variant is not in gnomAD v2.1.1, meeting PM2. Four individuals with this variant have been reported to have Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. These individuals are compound heterozygous for the variant and another pathogenic variant in GAA, either an 8 kb deletion extending from intron 7 to intron 15 (PMID 11854868; in trans, 1 point), c.2481+102_2646+31del (PMID 17616415; phase unknown), c.573C>A (p.Tyr191Ter) (PMID 11738358; phase unknown), and c.1942G>A (p.Gly648Ser) (PMID 29422078; note that in trans data from this patient will be used in the classification of p.Gly648Ser and is not included here in order to avoid a circular argument). This in trans data meets PM3_Strong. Another patient has been reported but was not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 28380188). There is a ClinVar entry for this variant (Variation ID: 188924, 1 star status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1_Moderate, PM2, PM3_Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274134/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAA NM_000152.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.35
• Publications: 9 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.2646+2T>A		splice_donor intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2646+2T>A		splice_donor intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2646+2T>A		splice_donor 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.2646+2T>A		splice_donor intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2646+2T>A		splice_donor intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2661+2T>A		splice_donor intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		5.4
GERP RS		5.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: -23
DS_DL_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204561; hg19: chr17-78092158;