rs142607078

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000378103.7(GBA2):c.1196G>C(p.Arg399Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,942 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

GBA2
ENST00000378103.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 2.98

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008438975).

BP6

Variant 9-35740296-C-G is Benign according to our data. Variant chr9-35740296-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241327.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr9-35740296-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00137 (209/152144) while in subpopulation NFE AF= 0.00248 (169/68034). AF 95% confidence interval is 0.00218. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA2	NM_020944.3 linkuse as main transcript	c.1196G>C	p.Arg399Pro	missense_variant	7/17	ENST00000378103.7	NP_065995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA2	ENST00000378103.7 linkuse as main transcript	c.1196G>C	p.Arg399Pro	missense_variant	7/17	1	NM_020944.3	ENSP00000367343	P1	Q9HCG7-1
GBA2	ENST00000378094.4 linkuse as main transcript	c.1196G>C	p.Arg399Pro	missense_variant	7/17	1		ENSP00000367334		Q9HCG7-2
GBA2	ENST00000467252.5 linkuse as main transcript	n.768G>C		non_coding_transcript_exon_variant	4/13	1

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00248

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00132

AC:

332

AN:

251210

Hom.:

AF XY:

0.00135

AC XY:

183

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00235

AC:

3435

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

1590

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00289

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152144

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

106

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00248

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00157

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GBA2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2021	Reported in an individual with sporadic spasticity, however, a second variant was not discussed and segregation studies were not provided (Ngo et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31692161) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2022	- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.9

DANN

Benign

0.76

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.41

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.0084

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.3

N;N

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

2.0

N;N

REVEL

Benign

0.020

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.16

MVP

0.40

MPC

0.41

ClinPred

0.0027

GERP RS

2.8

Varity_R

0.10

gMVP

0.70

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

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