NM_020944.3:c.2609G>C

Variant names:

• chr9-35737344-C-G
• rs199510198
• NM_020944.3:c.2609G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020944.3(GBA2):​c.2609G>C​(p.Arg870Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R870Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GBA2 NM_020944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• 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]

CREB3 (HGNC:2347): (cAMP responsive element binding protein 3) This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds to the cAMP-response element and regulates cell proliferation. The protein interacts with host cell factor C1, which also associates with the herpes simplex virus (HSV) protein VP16 that induces transcription of HSV immediate-early genes. This protein and VP16 both bind to the same site on host cell factor C1. It is thought that the interaction between this protein and host cell factor C1 plays a role in the establishment of latency during HSV infection. This protein also plays a role in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Additional transcript variants have been identified, but their biological validity has not been determined.[provided by RefSeq, Nov 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20681146).

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.2609G>C	p.Arg870Pro	missense	Exon 17 of 17	NP_065995.1
	GBA2	NM_001330660.2		c.*132G>C		3_prime_UTR	Exon 17 of 17	NP_001317589.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	ENST00000378103.7	TSL:1 MANE Select	c.2609G>C	p.Arg870Pro	missense	Exon 17 of 17	ENSP00000367343.3
	GBA2	ENST00000378094.4	TSL:1	c.*132G>C		3_prime_UTR	Exon 17 of 17	ENSP00000367334.4
	GBA2	ENST00000880894.1		c.2645G>C	p.Arg882Pro	missense	Exon 18 of 18	ENSP00000550953.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.1
DANN	Benign	0.97
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.52	P
Vest4		0.34
MVP		0.45
MPC		0.68
ClinPred		0.32	T
GERP RS		-5.5
Varity_R		0.21
gMVP		0.85
Mutation Taster		=76/24	polymorphism

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: rs199510198; hg19: chr9-35737341;