Genetic Variant NM_002868.4:c.24G>C (chr12-55986984-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002868.4(RAB5B):c.24G>C(p.Arg8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RAB5B
NM_002868.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

Publications

0 publications found

Variant links:

Genes affected

RAB5B (HGNC:9784): (RAB5B, member RAS oncogene family) Enables GDP binding activity; GTP-dependent protein binding activity; and GTPase activity. Involved in antigen processing and presentation and plasma membrane to endosome transport. Located in endosome and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB5B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28575486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5B	NM_002868.4 link	c.24G>C	p.Arg8Ser	missense_variant	Exon 2 of 6	ENST00000360299.10	NP_002859.1	P61020-1A0A024RB09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5B	ENST00000360299.10 link	c.24G>C	p.Arg8Ser	missense_variant	Exon 2 of 6	1	NM_002868.4	ENSP00000353444.5		P61020-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1409496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31960

American (AMR)

AF:

0.00

AC:

AN:

42912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24348

East Asian (EAS)

AF:

0.00

AC:

AN:

36234

South Asian (SAS)

AF:

0.00

AC:

AN:

85756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5452

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077758

Other (OTH)

AF:

0.00

AC:

AN:

56874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 25, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.24G>C (p.R8S) alteration is located in exon 2 (coding exon 1) of the RAB5B gene. This alteration results from a G to C substitution at nucleotide position 24, causing the arginine (R) at amino acid position 8 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

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.075

T;T;T;T;T;.;T

Eigen

Benign

0.012

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

.;D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.29

T;T;T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

-0.23

N;N;.;.;.;N;.

PhyloP100

1.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.2

N;N;N;D;N;N;.

REVEL

Benign

0.28

Sift

Uncertain

0.0020

D;D;D;D;D;D;.

Sift4G

Benign

0.20

T;T;T;D;T;T;T

Polyphen

0.0080

B;B;.;.;.;.;.

Vest4

0.64

MutPred

0.28

Loss of MoRF binding (P = 0.0035);Loss of MoRF binding (P = 0.0035);Loss of MoRF binding (P = 0.0035);.;Loss of MoRF binding (P = 0.0035);Loss of MoRF binding (P = 0.0035);Loss of MoRF binding (P = 0.0035);

MVP

0.73

MPC

1.3

ClinPred

0.83

GERP RS

4.9

PromoterAI

-0.10

Neutral

(source)

Varity_R

0.62

gMVP

0.49

Mutation Taster

=23/77

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over