rs34312177

Variant names:

• chr9-35748672-G-A
• rs34312177
• NM_020944.3:c.33C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020944.3(GBA2):​c.33C>T​(p.Thr11Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 1,586,674 control chromosomes in the GnomAD database, including 2,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (516 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1864 hom.)
• Consequence: GBA2 NM_020944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.143
• Publications: 6 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]

RGP1 (HGNC:21965): (RGP1 homolog, RAB6A GEF complex partner 1) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in negative regulation of cellular protein catabolic process; positive regulation of GTPase activity; and retrograde transport, endosome to Golgi. Located in cytosol and plasma membrane. Part of Ric1-Rgp1 guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-35748672-G-A is Benign according to our data. Variant chr9-35748672-G-A is described in ClinVar as Benign. ClinVar VariationId is 129139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.143 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	NM_020944.3	MANE Select	c.33C>T	p.Thr11Thr	synonymous	Exon 1 of 17	NP_065995.1
	GBA2	NM_001330660.2		c.33C>T	p.Thr11Thr	synonymous	Exon 1 of 17	NP_001317589.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	ENST00000378103.7	TSL:1 MANE Select	c.33C>T	p.Thr11Thr	synonymous	Exon 1 of 17	ENSP00000367343.3
	GBA2	ENST00000378094.4	TSL:1	c.33C>T	p.Thr11Thr	synonymous	Exon 1 of 17	ENSP00000367334.4
	GBA2	ENST00000880894.1		c.33C>T	p.Thr11Thr	synonymous	Exon 2 of 18	ENSP00000550953.1

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10065 AN: 152138 Hom.: 515 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0392 AC: 9188 AN: 234474 AF XY: 0.0372

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0452 AC: 64813 AN: 1434418 Hom.: 1864 Cov.: 31 AF XY: 0.0442 AC XY: 31361 AN XY: 710304

African (AFR) AF: 0.141 AC: 4601 AN: 32582

American (AMR) AF: 0.0247 AC: 1041 AN: 42194

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 381 AN: 24734

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39242

South Asian (SAS) AF: 0.0133 AC: 1102 AN: 82910

European-Finnish (FIN) AF: 0.0301 AC: 1588 AN: 52760

Middle Eastern (MID) AF: 0.0317 AC: 171 AN: 5392

European-Non Finnish (NFE) AF: 0.0487 AC: 53327 AN: 1095564

Other (OTH) AF: 0.0440 AC: 2598 AN: 59040

GnomAD4 genome AF: 0.0662 AC: 10075 AN: 152256 Hom.: 516 Cov.: 32 AF XY: 0.0640 AC XY: 4763 AN XY: 74448

African (AFR) AF: 0.137 AC: 5674 AN: 41524

American (AMR) AF: 0.0478 AC: 731 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4830

European-Finnish (FIN) AF: 0.0304 AC: 322 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3087 AN: 68022

Other (OTH) AF: 0.0615 AC: 130 AN: 2114

Alfa AF: 0.0542 Hom.: 569

Bravo AF: 0.0714

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34312177; hg19: chr9-35748669;