rs142607078

chr9-35740296-C-Gchr9-35740296-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020944.3(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 NM_020944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Benign. Variant got -9 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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA2	NM_020944.3	c.1196G>C	p.Arg399Pro	missense_variant	7/17	ENST00000378103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA2	ENST00000378103.7	c.1196G>C	p.Arg399Pro	missense_variant	7/17	1	NM_020944.3	P1
GBA2	ENST00000378094.4	c.1196G>C	p.Arg399Pro	missense_variant	7/17	1
GBA2	ENST00000467252.5	n.768G>C		non_coding_transcript_exon_variant	4/13	1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152144 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00135 AC XY: 183 AN XY: 135804

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.: 8 Cov.: 32 AF XY: 0.00219 AC XY: 1590 AN XY: 727216

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.: 0 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74334

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.: 0

Bravo AF: 0.00136

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	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	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2022	- -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

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	T
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	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	N;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs142607078; hg19: chr9-35740293; COSMIC: COSV99062010; COSMIC: COSV99062010;