rs28584995

Variant names:

• chr9-35741666-C-G
• rs28584995
• NM_020944.3:c.786+6G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-35741666-C-G
• chr9-35741666-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020944.3(GBA2):​c.786+6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,550,700 control chromosomes in the GnomAD database, including 32 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 0.0068 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (17 hom.)
• Consequence: GBA2 NM_020944.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003798
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113

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=-0.82).
• BP6: Variant 9-35741666-C-G is Benign according to our data. Variant chr9-35741666-C-G is described in ClinVar as [Benign]. Clinvar id is 241330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0068 (1035/152142) while in subpopulation AFR AF= 0.0234 (971/41476). AF 95% confidence interval is 0.0222. There are 15 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA2	NM_020944.3	c.786+6G>C		splice_region_variant, intron_variant	Intron 4 of 16	ENST00000378103.7	NP_065995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA2	ENST00000378103.7	c.786+6G>C		splice_region_variant, intron_variant	Intron 4 of 16	1	NM_020944.3	ENSP00000367343.3
GBA2	ENST00000378094.4	c.786+6G>C		splice_region_variant, intron_variant	Intron 4 of 16	1		ENSP00000367334.4
GBA2	ENST00000467252.5	n.358+6G>C		splice_region_variant, intron_variant	Intron 1 of 12	1
GBA2	ENST00000485259.1	n.371G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1032 AN: 152024 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00181 AC: 454 AN: 251316 Hom.: 3 AF XY: 0.00132 AC XY: 179 AN XY: 135840

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000713 AC: 997 AN: 1398558 Hom.: 17 Cov.: 25 AF XY: 0.000616 AC XY: 431 AN XY: 699364

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000705

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000854

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00680 AC: 1035 AN: 152142 Hom.: 15 Cov.: 32 AF XY: 0.00649 AC XY: 483 AN XY: 74390

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00203 Hom.: 2

Bravo AF: 0.00759

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
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: rs28584995; hg19: chr9-35741663;