Genetic Variant RAB8B:p.Arg203Leu (chr15-63263603-G-T) – 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_016530.3(RAB8B):c.608G>T(p.Arg203Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R203H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RAB8B
NM_016530.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.63

Publications

0 publications found

Variant links:

Genes affected

RAB8B (HGNC:30273): (RAB8B, member RAS oncogene family) RAB proteins, like RAB8B, are low molecular mass monomeric GTPases that localize on the cytoplasmic surfaces of distinct membrane-bound organelles. RAB proteins function in intracellular vesicle transport by aiding in the docking and/or fusion of vesicles with their target membranes (summary by Chen et al., 1997 [PubMed 9030196]).[supplied by OMIM, Nov 2010]

RAB8B 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=0.33925623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB8B	NM_016530.3 link	c.608G>T	p.Arg203Leu	missense_variant	Exon 8 of 8	ENST00000321437.9	NP_057614.1	Q92930
RAB8B	XM_017022312.1 link	c.365G>T	p.Arg122Leu	missense_variant	Exon 9 of 9		XP_016877801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB8B	ENST00000321437.9 link	c.608G>T	p.Arg203Leu	missense_variant	Exon 8 of 8	1	NM_016530.3	ENSP00000312734.4	Q92930
RAB8B	ENST00000558119.5 link	n.*388G>T		non_coding_transcript_exon_variant	Exon 9 of 9	2		ENSP00000453679.1	H0YMN7
RAB8B	ENST00000558119.5 link	n.*388G>T		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000453679.1	H0YMN7
RAB8B	ENST00000559927.1 link	n.*593G>T		downstream_gene_variant		5		ENSP00000453111.1	H0YL94

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456252

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724790

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106928

Other (OTH)

AF:

0.00

AC:

AN:

60210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.024

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.025

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.84

MutationAssessor

Benign

2.0

PhyloP100

3.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

REVEL

Benign

0.14

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.046

Polyphen

0.34

Vest4

0.48

MutPred

0.54

Loss of MoRF binding (P = 6e-04);

MVP

0.81

MPC

1.4

ClinPred

0.85

GERP RS

5.8

Varity_R

0.27

gMVP

0.71

Mutation Taster

=76/24

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over