chr6-57210299-G-A

Position:

chr6-57210299-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The ENST00000468148.6(RAB23):c.82C>T(p.Arg28Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RAB23
ENST00000468148.6 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.28

Variant links:

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]

RAB23 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-57210299-G-A is Pathogenic according to our data. Variant chr6-57210299-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280858.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB23	NM_016277.5 linkuse as main transcript	c.82C>T	p.Arg28Ter	stop_gained	2/7	ENST00000468148.6	NP_057361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6 linkuse as main transcript	c.82C>T	p.Arg28Ter	stop_gained	2/7	1	NM_016277.5	ENSP00000417610	P1
RAB23	ENST00000317483.4 linkuse as main transcript	c.82C>T	p.Arg28Ter	stop_gained	2/7	1		ENSP00000320413	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251340

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

RAB23-related Carpenter syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 20, 2017	The RAB23 c.82C>T (p.Arg28Ter) stop-gained variant has been reported in one study and is found in two brothers with Carpenter syndrome with the p.Arg28Ter and p.Leu145Ter variants on a complex allele. These variants are on the maternal allele and are in trans with p.Leu145Ter on the paternal allele (Jenkins et al. 2011). The clinically unaffected mother was confirmed to be a carrier of the complex allele. Control data are unavailable for this variant, which is reported at a frequency of 0.000025 in the Total population in the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants, the p.Arg28Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for Carpenter syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

RAB23-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2024

The RAB23 c.82C>T variant is predicted to result in premature protein termination (p.Arg28*). This variant has been reported in six individuals from three families with Carpenter syndrome (Jenkins et al. 2011. PubMed ID: 21412941; Ben-Salem et al. 2013. PubMed ID: 23599695; Lodhia et al. 2021. PubMed ID: 33368989). In two of those individuals from one family, the c.434T>A and c.82C>T variant were reported to be on the same allele (cis orientation) with a nonsense variant on the other allele (Jenkins et al. 2011. PubMed ID: 21412941). In another family, both parents were heterozygous for the c.82C>T variant and the child with Carpenter syndrome was homozygous for the c.82C>T variant (Lodhia et al. 2021. PubMed ID: 33368989). Chain-terminating variants in RAB23 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Carpenter syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

This sequence change creates a premature translational stop signal (p.Arg28*) in the RAB23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB23 are known to be pathogenic (PMID: 17503333, 21412941). This variant is present in population databases (rs765443042, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Carpenter syndrome, although in one family this variant was shown to be on the same chromosome (in cis) with another pathogenic variant (p.Leu145*) (PMID: 21412941, 23599695). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280858). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported previously in two siblings with Carpenter syndrome who harbored a maternally inherited R28X; L145X complex allele in trans with a paternally inherited L145X variant (Jenkins et al., 2011); This variant is associated with the following publications: (PMID: 23599695, 21412941, 33368989) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

A;A

Vest4

0.82

GERP RS

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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