rs113785628

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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

Publications

16 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):

complex hereditary spastic paraplegia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 46
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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=0.0065136254).

BP6

Variant 9-35740905-C-T is Benign according to our data. Variant chr9-35740905-C-T is described in ClinVar as Benign. ClinVar VariationId is 241331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	NM_020944.3	MANE Select	c.946G>A	p.Gly316Arg	missense	Exon 5 of 17	NP_065995.1	Q9HCG7-1
	GBA2	NM_001330660.2		c.946G>A	p.Gly316Arg	missense	Exon 5 of 17	NP_001317589.1	Q9HCG7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBA2	ENST00000378103.7	TSL:1 MANE Select	c.946G>A	p.Gly316Arg	missense	Exon 5 of 17	ENSP00000367343.3	Q9HCG7-1
GBA2	ENST00000378094.4	TSL:1	c.946G>A	p.Gly316Arg	missense	Exon 5 of 17	ENSP00000367334.4	Q9HCG7-2
GBA2	ENST00000467252.5	TSL:1	n.518G>A		non_coding_transcript_exon	Exon 2 of 13

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

GnomAD2 exomes

AF:

0.00756

AC:

1900

AN:

251370

AF XY:

0.00794

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 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

African (AFR)

AF:

0.00185

AC:

AN:

33478

American (AMR)

AF:

0.00273

AC:

122

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.00410

AC:

354

AN:

86256

European-Finnish (FIN)

AF:

0.0101

AC:

537

AN:

53418

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0113

AC:

12512

AN:

1111918

Other (OTH)

AF:

0.00767

AC:

463

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

773

1545

2318

3090

3863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.00711

AC:

1081

AN:

152070

Hom.:

Cov.:

AF XY:

0.00659

AC XY:

490

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00258

AC:

107

AN:

41454

American (AMR)

AF:

0.00366

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00773

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

811

AN:

67956

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

114

172

229

286

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:

0.00939

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia (1)

not specified (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Benign

0.19

Eigen_PC

Benign

0.069

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.0

PhyloP100

4.9

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.32

Sift

Benign

0.11

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.46

MVP

0.66

MPC

1.1

ClinPred

0.027

GERP RS

5.1

Varity_R

0.24

gMVP

0.69

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over