NM_000152.5:c.2189+1G>C

Variant names:

• chr17-80113367-G-C
• rs1209887739
• NM_000152.5:c.2189+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000152.5(GAA):​c.2189+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.41
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.2189+1G>C		splice_donor intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.2189+1G>C		splice_donor intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.2189+1G>C		splice_donor 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.2189+1G>C		splice_donor intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2189+1G>C		splice_donor intron	N/A	ENSP00000374665.3
	GAA	ENST00000933406.1		c.2204+1G>C		splice_donor intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421128 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 702310

African (AFR) AF: 0.00 AC: 0 AN: 32824

American (AMR) AF: 0.00 AC: 0 AN: 40322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24890

East Asian (EAS) AF: 0.00 AC: 0 AN: 37924

South Asian (SAS) AF: 0.00 AC: 0 AN: 81120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1089498

Other (OTH) AF: 0.00 AC: 0 AN: 58588

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.4
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs1209887739; hg19: chr17-78087166;