chr9-35738748-T-G

Variant names:

• chr9-35738748-T-G
• rs781668874
• NM_020944.3:c.1947+4A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020944.3(GBA2):​c.1947+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GBA2 NM_020944.3 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	NM_020944.3	MANE Select	c.1947+4A>C		splice_region intron	N/A	NP_065995.1
	GBA2	NM_001330660.2		c.1947+4A>C		splice_region intron	N/A	NP_001317589.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	ENST00000378103.7	TSL:1 MANE Select	c.1947+4A>C		splice_region intron	N/A	ENSP00000367343.3
	GBA2	ENST00000378094.4	TSL:1	c.1947+4A>C		splice_region intron	N/A	ENSP00000367334.4
	GBA2	ENST00000467252.5	TSL:1	n.1519+4A>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Benign	0.96
PhyloP100		3.1
PromoterAI		-0.0022	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -32
DS_DL_spliceai		0.48		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781668874; hg19: chr9-35738745;