chr9-35740225-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020944.3(GBA2):c.1267G>A(p.Gly423Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,614,110 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G423G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 35 hom. )

Consequence

GBA2
NM_020944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.73

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 46
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive cerebellar ataxia with late-onset spasticity
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GBA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022175312).

BP6

Variant 9-35740225-C-T is Benign according to our data. Variant chr9-35740225-C-T is described in ClinVar as Benign. ClinVar VariationId is 416639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1991/152254) while in subpopulation AFR AF = 0.0459 (1904/41522). AF 95% confidence interval is 0.0441. There are 44 homozygotes in GnomAd4. There are 932 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA2	NM_020944.3 link	c.1267G>A	p.Gly423Ser	missense_variant	Exon 7 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.1267G>A	p.Gly423Ser	missense_variant	Exon 7 of 17	1	NM_020944.3	ENSP00000367343.3	Q9HCG7-1
GBA2	ENST00000378094.4 link	c.1267G>A	p.Gly423Ser	missense_variant	Exon 7 of 17	1		ENSP00000367334.4	Q9HCG7-2
GBA2	ENST00000467252.5 link	n.839G>A		non_coding_transcript_exon_variant	Exon 4 of 13	1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1994

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00343

AC:

861

AN:

251230

AF XY:

0.00243

show subpopulations

Gnomad AFR exome

AF:

0.0477

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00129

AC:

1885

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

809

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0452

AC:

1514

AN:

33480

American (AMR)

AF:

0.00228

AC:

102

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000683

AC:

AN:

1111990

Other (OTH)

AF:

0.00296

AC:

179

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

110

220

330

440

550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0131

AC:

1991

AN:

152254

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

932

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0459

AC:

1904

AN:

41522

American (AMR)

AF:

0.00379

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68016

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00524

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0468

AC:

206

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

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

- -

Jul 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 01, 2017

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. -

Hereditary spastic paraplegia

Benign:1

Jun 16, 2021

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

0.080

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

PhyloP100

3.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.051

Sift

Benign

0.47

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0020

B;B

Vest4

0.14

MVP

0.60

MPC

0.30

ClinPred

0.0061

GERP RS

2.7

Varity_R

0.040

gMVP

0.86

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over