17-80117744-C-T

Variant names:

• chr17-80117744-C-T
• rs2039389671
• NM_000152.5:c.2476C>T
• GAA p.Leu826Leu

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000152.5(GAA):​c.2476C>T​(p.Leu826Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,608,278 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. L826L) has been classified as Likely benign. The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.438
• 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: ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 17-80117744-C-T is Benign according to our data. Variant chr17-80117744-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1079053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.438 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.2476C>T	p.Leu826Leu	synonymous	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2476C>T	p.Leu826Leu	synonymous	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2476C>T	p.Leu826Leu	synonymous	Exon 17 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.2476C>T	p.Leu826Leu	synonymous	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2476C>T	p.Leu826Leu	synonymous	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2491C>T	p.Leu831Leu	synonymous	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456074 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724126

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110534

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

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	-0.34
CADD	Benign	5.7
DANN	Benign	0.75
PhyloP100		0.44

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2039389671;

hg19: chr17-78091543;

COSMIC: COSV56412558;

COSMIC: COSV56412558;