NM_020944.3:c.2618G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_020944.3(GBA2):c.2618G>A(p.Arg873His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R873C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GBA2
NM_020944.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.58

Publications

8 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: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-35737336-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2585505.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 9-35737335-C-T is Pathogenic according to our data. Variant chr9-35737335-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 41490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA2	NM_020944.3 link	c.2618G>A	p.Arg873His	missense_variant	Exon 17 of 17	ENST00000378103.7	NP_065995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GBA2	ENST00000378103.7 link	c.2618G>A	p.Arg873His	missense_variant	Exon 17 of 17	1	NM_020944.3	ENSP00000367343.3
GBA2	ENST00000378094.4 link	c.*141G>A		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000367334.4
GBA2	ENST00000378088.1 link	c.*302G>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000367328.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111970

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000770

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 46

Pathogenic:2

Jan 25, 2019

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely pathogenic for Spastic paraplegia 46, autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate : Functional evidence PS3 downgraded in strength to Moderate (PMID:26220345). PP1 : Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23332917). PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

Feb 07, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Hereditary spastic paraplegia

Pathogenic:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.3

PhyloP100

7.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.96

ClinPred

1.0

GERP RS

5.9

Varity_R

0.80

gMVP

0.95

Mutation Taster

=7/93

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over