rs61736894

Variant names:

• chr17-80118291-C-T
• rs61736894
• NM_000152.5:c.2580C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-80118291-C-T
• chr17-80118291-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000152.5(GAA):​c.2580C>T​(p.Asp860Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,598,350 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.48
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-80118291-C-T is Benign according to our data. Variant chr17-80118291-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00429 (653/152232) while in subpopulation AFR AF = 0.0151 (628/41526). AF 95% confidence interval is 0.0141. There are 5 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.2580C>T	p.Asp860Asp	synonymous	Exon 18 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2580C>T	p.Asp860Asp	synonymous	Exon 19 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2580C>T	p.Asp860Asp	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.2580C>T	p.Asp860Asp	synonymous	Exon 18 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2580C>T	p.Asp860Asp	synonymous	Exon 19 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2595C>T	p.Asp865Asp	synonymous	Exon 18 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152114 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00112 AC: 266 AN: 237260 AF XY: 0.000756

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.000237

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000557

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000437 AC: 632 AN: 1446118 Hom.: 5 Cov.: 35 AF XY: 0.000364 AC XY: 261 AN XY: 717648

African (AFR) AF: 0.0160 AC: 529 AN: 33066

American (AMR) AF: 0.000349 AC: 15 AN: 42964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.0000828 AC: 7 AN: 84498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000218 AC: 24 AN: 1103230

Other (OTH) AF: 0.000957 AC: 57 AN: 59576

GnomAD4 genome AF: 0.00429 AC: 653 AN: 152232 Hom.: 5 Cov.: 32 AF XY: 0.00410 AC XY: 305 AN XY: 74436

African (AFR) AF: 0.0151 AC: 628 AN: 41526

American (AMR) AF: 0.000915 AC: 14 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.00492

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease, type II (4)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.20
DANN	Benign	0.32
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs61736894; hg19: chr17-78092090; COSMIC: COSV108836811; COSMIC: COSV108836811;