rs41292410

Positions:

• chr17-80118396-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000302262.8(GAA):​c.2646+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,555,594 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (25 hom.)
• Consequence: GAA ENST00000302262.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.985

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-80118396-G-A is Benign according to our data. Variant chr17-80118396-G-A is described in ClinVar as [Benign]. Clinvar id is 495667.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2646+39G>A		intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2646+39G>A		intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 515 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00301 AC: 610 AN: 202470 Hom.: 2 AF XY: 0.00322 AC XY: 346 AN XY: 107492

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.000742

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.00267

Gnomad FIN exome AF: 0.00355

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00415 AC: 5822 AN: 1403294 Hom.: 25 Cov.: 34 AF XY: 0.00422 AC XY: 2918 AN XY: 690818

Gnomad4 AFR exome AF: 0.000372

Gnomad4 AMR exome AF: 0.000555

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00397

Gnomad4 NFE exome AF: 0.00479

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74466

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00584

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00490 Hom.: 0

Bravo AF: 0.00298

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 04, 2019

Variant summary: GAA c.2646+39G>A is located at a position not widely known to affect splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. TThe variant allele was found at a frequency of 0.003 in 202470 control chromosomes (including 2 homozygotes), predominantly at a frequency of 0.0048 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2646+39G>A in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.77
DANN	Benign	0.58

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: rs41292410; hg19: chr17-78092195;