chr1-220182842-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_012414.4(RAB3GAP2):c.2088A>G(p.Thr696Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,613,554 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 286 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 266 hom. )

Consequence

RAB3GAP2
NM_012414.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.613

Publications

3 publications found

Variant links:

Genes affected

RAB3GAP2 (HGNC:17168): (RAB3 GTPase activating non-catalytic protein subunit 2) The protein encoded by this gene belongs to the RAB3 protein family, members of which are involved in regulated exocytosis of neurotransmitters and hormones. This protein forms the Rab3 GTPase-activating complex with RAB3GAP1, where it constitutes the regulatory subunit, whereas the latter functions as the catalytic subunit. This gene has the highest level of expression in the brain, consistent with it having a key role in neurodevelopment. Mutations in this gene are associated with Martsolf syndrome.[provided by RefSeq, Oct 2009]

RAB3GAP2 Gene-Disease associations (from GenCC):

Martsolf syndrome 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
RAB18 deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
Warburg micro syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Warburg micro syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal recessive spastic paraplegia type 69
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cataract-intellectual disability-hypogonadism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAB3GAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-220182842-T-C is Benign according to our data. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-220182842-T-C is described in CliVar as Benign. Clinvar id is 130077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.613 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3GAP2	NM_012414.4 link	c.2088A>G	p.Thr696Thr	synonymous_variant	Exon 20 of 35	ENST00000358951.7	NP_036546.2	Q9H2M9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB3GAP2	ENST00000358951.7 link	c.2088A>G	p.Thr696Thr	synonymous_variant	Exon 20 of 35	1	NM_012414.4	ENSP00000351832.2		Q9H2M9-1

Frequencies

GnomAD3 genomes

AF:

0.0337

AC:

5135

AN:

152200

Hom.:

287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00941

AC:

2363

AN:

251194

AF XY:

0.00729

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.00634

Gnomad ASJ exome

AF:

0.0137

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000519

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00378

AC:

5518

AN:

1461236

Hom.:

266

Cov.:

AF XY:

0.00335

AC XY:

2439

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.118

AC:

3942

AN:

33454

American (AMR)

AF:

0.00682

AC:

305

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

351

AN:

26118

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39598

South Asian (SAS)

AF:

0.000197

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00975

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000291

AC:

323

AN:

1111638

Other (OTH)

AF:

0.00840

AC:

507

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

238

476

714

952

1190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.0337

AC:

5129

AN:

152318

Hom.:

286

Cov.:

AF XY:

0.0331

AC XY:

2463

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.115

AC:

4788

AN:

41552

American (AMR)

AF:

0.0131

AC:

200

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68026

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

234

467

701

934

1168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0171

Hom.:

Bravo

AF:

0.0386

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Warburg micro syndrome 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Martsolf syndrome;C3280214:Warburg micro syndrome 2

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Martsolf syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.9

(source)

DANN

Benign

0.69

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over