rs73438754

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020944.3(GBA2):​c.1795+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00793 in 1,610,666 control chromosomes in the GnomAD database, including 431 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 0.031 ( 214 hom., cov: 32)
Exomes 𝑓: 0.0055 ( 217 hom. )

Consequence

GBA2
NM_020944.3 splice_region, intron

Scores

2
Splicing: ADA: 0.0001650
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.00100

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 9-35738995-C-T is Benign according to our data. Variant chr9-35738995-C-T is described in ClinVar as Benign. ClinVar VariationId is 416641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GBA2
NM_020944.3
MANE Select
c.1795+7G>A
splice_region intron
N/ANP_065995.1
GBA2
NM_001330660.2
c.1795+7G>A
splice_region intron
N/ANP_001317589.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GBA2
ENST00000378103.7
TSL:1 MANE Select
c.1795+7G>A
splice_region intron
N/AENSP00000367343.3
GBA2
ENST00000378094.4
TSL:1
c.1795+7G>A
splice_region intron
N/AENSP00000367334.4
GBA2
ENST00000467252.5
TSL:1
n.1367+7G>A
splice_region intron
N/A

Frequencies

GnomAD3 genomes
AF:
0.0312
AC:
4737
AN:
152062
Hom.:
214
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0136
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00226
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00232
Gnomad OTH
AF:
0.0206
GnomAD2 exomes
AF:
0.00940
AC:
2347
AN:
249766
AF XY:
0.00705
show subpopulations
Gnomad AFR exome
AF:
0.110
Gnomad AMR exome
AF:
0.00564
Gnomad ASJ exome
AF:
0.000299
Gnomad EAS exome
AF:
0.0000546
Gnomad FIN exome
AF:
0.00358
Gnomad NFE exome
AF:
0.00225
Gnomad OTH exome
AF:
0.00608
GnomAD4 exome
AF:
0.00550
AC:
8020
AN:
1458486
Hom.:
217
Cov.:
31
AF XY:
0.00487
AC XY:
3534
AN XY:
725554
show subpopulations
African (AFR)
AF:
0.106
AC:
3548
AN:
33410
American (AMR)
AF:
0.00598
AC:
267
AN:
44638
Ashkenazi Jewish (ASJ)
AF:
0.000306
AC:
8
AN:
26102
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39666
South Asian (SAS)
AF:
0.000314
AC:
27
AN:
86066
European-Finnish (FIN)
AF:
0.00435
AC:
232
AN:
53378
Middle Eastern (MID)
AF:
0.00782
AC:
45
AN:
5756
European-Non Finnish (NFE)
AF:
0.00306
AC:
3389
AN:
1109212
Other (OTH)
AF:
0.00835
AC:
503
AN:
60258
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
421
842
1263
1684
2105
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
202
404
606
808
1010
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0312
AC:
4754
AN:
152180
Hom.:
214
Cov.:
32
AF XY:
0.0300
AC XY:
2231
AN XY:
74408
show subpopulations
African (AFR)
AF:
0.104
AC:
4319
AN:
41470
American (AMR)
AF:
0.0135
AC:
207
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.000621
AC:
3
AN:
4828
European-Finnish (FIN)
AF:
0.00226
AC:
24
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00232
AC:
158
AN:
68006
Other (OTH)
AF:
0.0204
AC:
43
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
218
435
653
870
1088
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
52
104
156
208
260
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0155
Hom.:
58
Bravo
AF:
0.0354
Asia WGS
AF:
0.00606
AC:
22
AN:
3478
EpiCase
AF:
0.00142
EpiControl
AF:
0.00202

ClinVar

ClinVar submissions as Germline

Significance:Benign
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
1
Hereditary spastic paraplegia (1)
-
-
1
not provided (1)
-
-
1
not specified (1)
-
-
1
Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
6.4
DANN
Benign
0.75
PhyloP100
-0.0010
PromoterAI
-0.0056
Neutral
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00017
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

Other links and lift over

dbSNP: rs73438754; hg19: chr9-35738992; COSMIC: COSV105274190; COSMIC: COSV105274190; API