Genetic Variant RAB26:p.Pro28Ser (chr16-2148865-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014353.5(RAB26):c.82C>T(p.Pro28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,402,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

RAB26
NM_014353.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.963

Variant links:

Genes affected

RAB26 (HGNC:14259): (RAB26, member RAS oncogene family) Members of the RAB protein family, including RAB26, are important regulators of vesicular fusion and trafficking. The RAB family of small G proteins regulates intercellular vesicle trafficking, including exocytosis, endocytosis, and recycling (summary by Seki et al., 2000 [PubMed 11043516]).[supplied by OMIM, Nov 2010]

RAB26 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008869141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB26	NM_014353.5 link	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 9	ENST00000210187.11	NP_055168.2	Q9ULW5-1
RAB26	NM_001308053.1 link	c.-117C>T		5_prime_UTR_variant	Exon 2 of 10		NP_001294982.1	Q9ULW5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB26	ENST00000210187.11 link	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 9	1	NM_014353.5	ENSP00000210187.6		Q9ULW5-1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000327

AC:

AN:

61178

Hom.:

AF XY:

0.000247

AC XY:

AN XY:

36430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000456

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000413

Gnomad OTH exome

AF:

0.00123

GnomAD4 exome

AF:

0.000103

AC:

129

AN:

1250812

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

614084

show subpopulations

Gnomad4 AFR exome

AF:

0.00190

Gnomad4 AMR exome

AF:

0.000317

Gnomad4 ASJ exome

AF:

0.00146

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000159

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.000513

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000536

ExAC

AF:

0.0000793

AC:

Asia WGS

AF:

0.000291

AC:

AN:

3454

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82C>T (p.P28S) alteration is located in exon 1 (coding exon 1) of the RAB26 gene. This alteration results from a C to T substitution at nucleotide position 82, causing the proline (P) at amino acid position 28 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

0.074

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.3

DANN

Benign

0.69

DEOGEN2

Benign

0.016

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.0089

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.26

REVEL

Benign

0.026

Sift

Benign

0.16

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.077

MutPred

0.22

Gain of phosphorylation at P28 (P = 0.0087);

MVP

0.22

MPC

0.17

ClinPred

0.016

GERP RS

2.0

Varity_R

0.035

gMVP

0.34

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