rs2304837

chr17-80112732-G-Achr17-80112732-G-Cchr17-80112732-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):c.1888+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,598,582 control chromosomes in the GnomAD database, including 2,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (308 hom., cov: 33)
  • Exomes 𝑓: 0.046 (2665 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.474

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-80112732-G-A is Benign according to our data. Variant chr17-80112732-G-A is described in ClinVar as [Benign]. Clinvar id is 255357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80112732-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1888+21G>A		intron_variant		ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1888+21G>A		intron_variant		1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6643 AN: 152178 Hom.: 305 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.0687

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0395

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0577 AC: 12313 AN: 213296 Hom.: 682 AF XY: 0.0577 AC XY: 6743 AN XY: 116894

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0268

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.0644

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0591

GnomAD4 exome AF: 0.0458 AC: 66311 AN: 1446286 Hom.: 2665 Cov.: 33 AF XY: 0.0465 AC XY: 33394 AN XY: 718268

Gnomad4 AFR exome AF: 0.0196

Gnomad4 AMR exome AF: 0.0276

Gnomad4 ASJ exome AF: 0.0427

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.0618

Gnomad4 FIN exome AF: 0.0679

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0525

GnomAD4 genome AF: 0.0437 AC: 6657 AN: 152296 Hom.: 308 Cov.: 33 AF XY: 0.0455 AC XY: 3386 AN XY: 74470

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0389

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.0689

Gnomad4 FIN AF: 0.0652

Gnomad4 NFE AF: 0.0395

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0286 Hom.: 28

Bravo AF: 0.0399

Asia WGS AF: 0.155 AC: 541 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 08, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.3
Dann	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs2304837; hg19: chr17-78086531; COSMIC: COSV56407589; COSMIC: COSV56407589;