rs1040461

chr6-57190556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016277.5(RAB23):c.619G>A(p.Gly207Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0867 in 1,613,576 control chromosomes in the GnomAD database, including 7,009 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1220 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5789 hom.)
• Consequence: RAB23 NM_016277.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.99

Genes affected

RAB23 (HGNC:14263): (RAB23, member RAS oncogene family) This gene encodes a small GTPase of the Ras superfamily. Rab proteins are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. The encoded protein may play a role in central nervous system development by antagonizing sonic hedgehog signaling. Disruption of this gene has been implicated in Carpenter syndrome as well as cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012622476).
• BP6: Variant 6-57190556-C-T is Benign according to our data. Variant chr6-57190556-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 357640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB23	NM_016277.5	c.619G>A	p.Gly207Ser	missense_variant	7/7	ENST00000468148.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB23	ENST00000468148.6	c.619G>A	p.Gly207Ser	missense_variant	7/7	1	NM_016277.5	P1
RAB23	ENST00000317483.4	c.619G>A	p.Gly207Ser	missense_variant	7/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17523 AN: 152020 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.0951

Gnomad SAS AF: 0.0798

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0931

GnomAD3 exomes AF: 0.0983 AC: 24708 AN: 251284 Hom.: 1455 AF XY: 0.0948 AC XY: 12873 AN XY: 135812

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.0370

Gnomad EAS exome AF: 0.0950

Gnomad SAS exome AF: 0.0794

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.0811

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0837 AC: 122294 AN: 1461438 Hom.: 5789 Cov.: 31 AF XY: 0.0829 AC XY: 60244 AN XY: 727036

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.0361

Gnomad4 EAS exome AF: 0.0669

Gnomad4 SAS exome AF: 0.0764

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.0789

Gnomad4 OTH exome AF: 0.0831

GnomAD4 genome AF: 0.115 AC: 17558 AN: 152138 Hom.: 1220 Cov.: 32 AF XY: 0.116 AC XY: 8649 AN XY: 74368

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.0871

Gnomad4 ASJ AF: 0.0377

Gnomad4 EAS AF: 0.0953

Gnomad4 SAS AF: 0.0797

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.0825

Gnomad4 OTH AF: 0.0936

Alfa AF: 0.0810 Hom.: 1372

Bravo AF: 0.112

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0794 AC: 306

ESP6500AA AF: 0.183 AC: 806

ESP6500EA AF: 0.0802 AC: 690

ExAC AF: 0.0979 AC: 11887

Asia WGS AF: 0.111 AC: 384 AN: 3478

EpiCase AF: 0.0740

EpiControl AF: 0.0697

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carpenter syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

RAB23-related Carpenter syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 03, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

This variant is associated with the following publications: (PMID: 29416296) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	15
Dann	Benign	0.84
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.15	T;.
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	B;B
Vest4		0.049
MPC		0.18
ClinPred		0.018	T
GERP RS		5.8
Varity_R		0.097
gMVP		0.23

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

Other links and lift over

dbSNP: rs1040461; hg19: chr6-57055354; COSMIC: COSV58097895; COSMIC: COSV58097895;