Genetic Variant RAB2B:p.Leu175Ser (chr14-21462369-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032846.4(RAB2B):c.524T>C(p.Leu175Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 1 hom. )

Consequence

RAB2B
NM_032846.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71

Variant links:

Genes affected

RAB2B (HGNC:20246): (RAB2B, member RAS oncogene family) Members of the Rab protein family are nontransforming monomeric GTP-binding proteins of the Ras superfamily that contain 4 highly conserved regions involved in GTP binding and hydrolysis. Rab proteins are prenylated, membrane-bound proteins involved in vesicular fusion and trafficking; see MIM 179508.[supplied by OMIM, Apr 2006]

RAB2B links:

LOC124903283 (HGNC:):

LOC124903283 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1286645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB2B	NM_032846.4 link	c.524T>C	p.Leu175Ser	missense_variant	Exon 7 of 8	ENST00000397762.6	NP_116235.2	Q8WUD1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB2B	ENST00000397762.6 link	c.524T>C	p.Leu175Ser	missense_variant	Exon 7 of 8	1	NM_032846.4	ENSP00000380869.1		Q8WUD1-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250882

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000200

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524T>C (p.L175S) alteration is located in exon 7 (coding exon 7) of the RAB2B gene. This alteration results from a T to C substitution at nucleotide position 524, causing the leucine (L) at amino acid position 175 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.056

T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.086

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.55

N;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;.

REVEL

Benign

0.23

Sift

Benign

0.68

T;.

Sift4G

Benign

0.71

T;.

Polyphen

0.0010

B;.

Vest4

0.34

MVP

0.64

MPC

0.78

ClinPred

0.081

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.098

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over