9-35740049-G-T

Position:

chr9-35740049-G-T

Variant summary

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

The NM_020944.3(GBA2):c.1358C>A(p.Ala453Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,614,066 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A453T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 20 hom. )

Consequence

GBA2
NM_020944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.936

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:

GBA2 (HGNC:):

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=0.0031112432).

BP6

Variant 9-35740049-G-T is Benign according to our data. Variant chr9-35740049-G-T is described in ClinVar as [Benign]. Clinvar id is 458299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35740049-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00113 (172/152212) while in subpopulation EAS AF= 0.0299 (154/5158). AF 95% confidence interval is 0.026. There are 4 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA2	NM_020944.3 linkuse as main transcript	c.1358C>A	p.Ala453Glu	missense_variant	8/17	ENST00000378103.7	NP_065995.1	Q9HCG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GBA2	ENST00000378103.7 linkuse as main transcript	c.1358C>A	p.Ala453Glu	missense_variant	8/17	1	NM_020944.3	ENSP00000367343.3	Q9HCG7-1
GBA2	ENST00000378094.4 linkuse as main transcript	c.1358C>A	p.Ala453Glu	missense_variant	8/17	1		ENSP00000367334.4	Q9HCG7-2
GBA2	ENST00000467252.5 linkuse as main transcript	n.930C>A		non_coding_transcript_exon_variant	5/13	1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0296

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00211

AC:

531

AN:

251402

Hom.:

AF XY:

0.00185

AC XY:

252

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0279

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000811

AC:

1186

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000804

AC XY:

585

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0263

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152212

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0299

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00130

ExAC

AF:

0.00205

AC:

249

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2019

- -

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

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.99

L;L

PrimateAI

Benign

0.34

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.060

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;B

Vest4

0.22

MVP

0.39

MPC

0.34

ClinPred

0.0019

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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