9-35740905-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020944.3(GBA2):c.946G>A(p.Gly316Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00939 in 1,613,850 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 94 hom. )

Consequence

GBA2
NM_020944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.86

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065136254).

BP6

Variant 9-35740905-C-T is Benign according to our data. Variant chr9-35740905-C-T is described in ClinVar as [Benign]. Clinvar id is 241331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35740905-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00711 (1081/152070) while in subpopulation NFE AF= 0.0119 (811/67956). AF 95% confidence interval is 0.0113. There are 9 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA2	NM_020944.3 link	c.946G>A	p.Gly316Arg	missense_variant	Exon 5 of 17	ENST00000378103.7	NP_065995.1	Q9HCG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GBA2	ENST00000378103.7 link	c.946G>A	p.Gly316Arg	missense_variant	Exon 5 of 17	1	NM_020944.3	ENSP00000367343.3	Q9HCG7-1
GBA2	ENST00000378094.4 link	c.946G>A	p.Gly316Arg	missense_variant	Exon 5 of 17	1		ENSP00000367334.4	Q9HCG7-2
GBA2	ENST00000467252.5 link	n.518G>A		non_coding_transcript_exon_variant	Exon 2 of 13	1

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1080

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00259

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00756

AC:

1900

AN:

251370

Hom.:

AF XY:

0.00794

AC XY:

1079

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00376

Gnomad FIN exome

AF:

0.00901

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.00733

GnomAD4 exome

AF:

0.00963

AC:

14070

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00966

AC XY:

7022

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00410

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.0113

Gnomad4 OTH exome

AF:

0.00767

GnomAD4 genome

AF:

0.00711

AC:

1081

AN:

152070

Hom.:

Cov.:

AF XY:

0.00659

AC XY:

490

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00679

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00803

AC:

975

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA2: BP4, BS1, BS2 -

not specified

Benign:1

May 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jan 04, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.

Eigen

Benign

0.19

Eigen_PC

Benign

0.069

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0065

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.32

Sift

Benign

0.11

T;T

Sift4G

Uncertain

0.028

D;D

Polyphen

1.0

D;D

Vest4

0.46

MVP

0.66

MPC

1.1

ClinPred

0.027

GERP RS

5.1

Varity_R

0.24

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over