rs34312177

Positions:

• chr9-35748672-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020944.3(GBA2):​c.33C>T​(p.Thr11Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 1,586,674 control chromosomes in the GnomAD database, including 2,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (516 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1864 hom.)
• Consequence: GBA2 NM_020944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.143

Genes affected

GBA2 (HGNC:18986): (glucosylceramidase beta 2) This gene encodes a microsomal beta-glucosidase that catalyzes the hydrolysis of bile acid 3-O-glucosides as endogenous compounds. Studies to determine subcellular localization of this protein in the liver indicated that the enzyme was mainly enriched in the microsomal fraction where it appeared to be confined to the endoplasmic reticulum. This putative transmembrane protein is thought to play a role in carbohydrate transport and metabolism. [provided by RefSeq, Jul 2008]

GBA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-35748672-G-A is Benign according to our data. Variant chr9-35748672-G-A is described in ClinVar as [Benign]. Clinvar id is 129139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35748672-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.143 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA2	NM_020944.3	c.33C>T	p.Thr11Thr	synonymous_variant	1/17	ENST00000378103.7	NP_065995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA2	ENST00000378103.7	c.33C>T	p.Thr11Thr	synonymous_variant	1/17	1	NM_020944.3	ENSP00000367343.3
GBA2	ENST00000378094.4	c.33C>T	p.Thr11Thr	synonymous_variant	1/17	1		ENSP00000367334.4
GBA2	ENST00000489025.1	n.302C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10065 AN: 152138 Hom.: 515 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0621

GnomAD3 exomes AF: 0.0392 AC: 9188 AN: 234474 Hom.: 341 AF XY: 0.0372 AC XY: 4701 AN XY: 126334

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0452 AC: 64813 AN: 1434418 Hom.: 1864 Cov.: 31 AF XY: 0.0442 AC XY: 31361 AN XY: 710304

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0487

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0662 AC: 10075 AN: 152256 Hom.: 516 Cov.: 32 AF XY: 0.0640 AC XY: 4763 AN XY: 74448

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0478

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0304

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0615

Alfa AF: 0.0566 Hom.: 148

Bravo AF: 0.0714

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs34312177; hg19: chr9-35748669;