rs73438754

chr9-35738995-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020944.3(GBA2):c.1795+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00793 in 1,610,666 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (214 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (217 hom.)
• Consequence: GBA2 NM_020944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001650
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-35738995-C-T is Benign according to our data. Variant chr9-35738995-C-T is described in ClinVar as [Benign]. Clinvar id is 416641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA2	NM_020944.3	c.1795+7G>A		splice_region_variant, intron_variant		ENST00000378103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA2	ENST00000378103.7	c.1795+7G>A		splice_region_variant, intron_variant		1	NM_020944.3	P1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4737 AN: 152062 Hom.: 214 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00940 AC: 2347 AN: 249766 Hom.: 84 AF XY: 0.00705 AC XY: 952 AN XY: 135002

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00358

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00608

GnomAD4 exome AF: 0.00550 AC: 8020 AN: 1458486 Hom.: 217 Cov.: 31 AF XY: 0.00487 AC XY: 3534 AN XY: 725554

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.00598

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00435

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.0312 AC: 4754 AN: 152180 Hom.: 214 Cov.: 32 AF XY: 0.0300 AC XY: 2231 AN XY: 74408

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0155 Hom.: 58

Bravo AF: 0.0354

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2017

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	6.4
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0
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: rs73438754; hg19: chr9-35738992; COSMIC: COSV105274190; COSMIC: COSV105274190;