17-80105844-C-T

Variant names:

• chr17-80105844-C-T
• rs1800301
• NM_000152.5:c.642C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000152.5(GAA):​c.642C>T​(p.Ser214Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,608,148 control chromosomes in the GnomAD database, including 35,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S214S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2499 hom., cov: 34)
  • Exomes 𝑓: 0.21 (32917 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -3.21
• Publications: 23 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=-0.69).
• BP6: Variant 17-80105844-C-T is Benign according to our data. Variant chr17-80105844-C-T is described in ClinVar as Benign. ClinVar VariationId is 92487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

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.642C>T	p.Ser214Ser	synonymous	Exon 3 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.642C>T	p.Ser214Ser	synonymous	Exon 4 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.642C>T	p.Ser214Ser	synonymous	Exon 3 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.642C>T	p.Ser214Ser	synonymous	Exon 3 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.642C>T	p.Ser214Ser	synonymous	Exon 4 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000714054.1		c.-160C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	ENSP00000519344.1	A0AAQ5BHE1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25227 AN: 152116 Hom.: 2502 Cov.: 34

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.178 AC: 43932 AN: 246290 AF XY: 0.187

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.206 AC: 299792 AN: 1455914 Hom.: 32917 Cov.: 56 AF XY: 0.206 AC XY: 149517 AN XY: 724492

African (AFR) AF: 0.0714 AC: 2390 AN: 33464

American (AMR) AF: 0.105 AC: 4689 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7763 AN: 26132

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39698

South Asian (SAS) AF: 0.174 AC: 15041 AN: 86242

European-Finnish (FIN) AF: 0.245 AC: 11779 AN: 48078

Middle Eastern (MID) AF: 0.304 AC: 1706 AN: 5604

European-Non Finnish (NFE) AF: 0.220 AC: 244367 AN: 1111662

Other (OTH) AF: 0.199 AC: 12035 AN: 60326

GnomAD4 genome AF: 0.166 AC: 25225 AN: 152234 Hom.: 2499 Cov.: 34 AF XY: 0.165 AC XY: 12318 AN XY: 74432

African (AFR) AF: 0.0741 AC: 3077 AN: 41550

American (AMR) AF: 0.136 AC: 2076 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5190

South Asian (SAS) AF: 0.165 AC: 799 AN: 4830

European-Finnish (FIN) AF: 0.249 AC: 2629 AN: 10578

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15011 AN: 68004

Other (OTH) AF: 0.171 AC: 361 AN: 2114

Alfa AF: 0.178 Hom.: 1061

Bravo AF: 0.154

Asia WGS AF: 0.0710 AC: 250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.40
DANN	Benign	0.94
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800301; hg19: chr17-78079643; COSMIC: COSV56407138; COSMIC: COSV56407138;