rs142621039

Variant names:

• chr9-35738149-C-T
• rs142621039
• NM_020944.3:c.2201G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_020944.3(GBA2):​c.2201G>A​(p.Arg734His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,613,488 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R734S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: GBA2 NM_020944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.27
• Publications: 5 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08138573).
• BP6: Variant 9-35738149-C-T is Benign according to our data. Variant chr9-35738149-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458301.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00046 (70/152302) while in subpopulation NFE AF = 0.000618 (42/68014). AF 95% confidence interval is 0.000469. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.2201G>A	p.Arg734His	missense	Exon 15 of 17	NP_065995.1	Q9HCG7-1
	GBA2	NM_001330660.2		c.2201G>A	p.Arg734His	missense	Exon 15 of 17	NP_001317589.1	Q9HCG7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA2	ENST00000378103.7	TSL:1 MANE Select	c.2201G>A	p.Arg734His	missense	Exon 15 of 17	ENSP00000367343.3	Q9HCG7-1
	GBA2	ENST00000378094.4	TSL:1	c.2201G>A	p.Arg734His	missense	Exon 15 of 17	ENSP00000367334.4	Q9HCG7-2
	GBA2	ENST00000467252.5	TSL:1	n.1773G>A		non_coding_transcript_exon	Exon 12 of 13

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000668 AC: 168 AN: 251416 AF XY: 0.000743

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000606 AC: 885 AN: 1461186 Hom.: 10 Cov.: 32 AF XY: 0.000620 AC XY: 451 AN XY: 726922

African (AFR) AF: 0.00123 AC: 41 AN: 33468

American (AMR) AF: 0.00103 AC: 46 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86240

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53420

Middle Eastern (MID) AF: 0.0281 AC: 162 AN: 5764

European-Non Finnish (NFE) AF: 0.000428 AC: 476 AN: 1111376

Other (OTH) AF: 0.00154 AC: 93 AN: 60370

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74468

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000954 Hom.: 7

Bravo AF: 0.000559

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GBA2-related disorder (1)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.76	N
PhyloP100		3.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.062
Sift	Benign	0.049	D
Sift4G	Benign	0.15	T
Polyphen		0.040	B
Vest4		0.18
MVP		0.67
MPC		0.37
ClinPred		0.010	T
GERP RS		4.9
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.18
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142621039; hg19: chr9-35738146; COSMIC: COSV107439561; COSMIC: COSV107439561;