chr17-80118319-C-A

Variant names:

• chr17-80118319-C-A
• rs780321415
• NM_000152.5:c.2608C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000152.5(GAA):​c.2608C>A​(p.Arg870Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,581,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R870R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.218
• Publications: 25 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-80118319-C-A is Benign according to our data. Variant chr17-80118319-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1142659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.218 with no splicing effect.

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.2608C>A	p.Arg870Arg	synonymous	Exon 18 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2608C>A	p.Arg870Arg	synonymous	Exon 19 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2608C>A	p.Arg870Arg	synonymous	Exon 18 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.2608C>A	p.Arg870Arg	synonymous	Exon 18 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2608C>A	p.Arg870Arg	synonymous	Exon 19 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2623C>A	p.Arg875Arg	synonymous	Exon 18 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1429602 Hom.: 0 Cov.: 35 AF XY: 0.00000141 AC XY: 1 AN XY: 707142

African (AFR) AF: 0.00 AC: 0 AN: 32776

American (AMR) AF: 0.00 AC: 0 AN: 41830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23690

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 81756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093896

Other (OTH) AF: 0.00 AC: 0 AN: 58844

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Glycogen storage disease, type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.4
DANN	Benign	0.56
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs780321415; hg19: chr17-78092118;