6-57194765-T-C

Variant names:

• chr6-57194765-T-C
• rs150762175
• NM_016277.5:c.481+5A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016277.5(RAB23):​c.481+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,596,234 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: RAB23 NM_016277.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004387
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.697
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• RAB23-related Carpenter syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-57194765-T-C is Benign according to our data. Variant chr6-57194765-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 463375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00235 (358/152264) while in subpopulation AFR AF = 0.0083 (345/41574). AF 95% confidence interval is 0.00758. There are 0 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB23	NM_016277.5	c.481+5A>G		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000468148.6	NP_057361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6	c.481+5A>G		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_016277.5	ENSP00000417610.1
RAB23	ENST00000317483.4	c.481+5A>G		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000320413.3

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000650 AC: 162 AN: 249354 AF XY: 0.000490

Gnomad AFR exome AF: 0.00884

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000248 AC: 358 AN: 1443970 Hom.: 3 Cov.: 28 AF XY: 0.000204 AC XY: 147 AN XY: 719300

African (AFR) AF: 0.00848 AC: 281 AN: 33134

American (AMR) AF: 0.000606 AC: 27 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.000872 AC: 5 AN: 5734

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1096544

Other (OTH) AF: 0.000553 AC: 33 AN: 59728

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74462

African (AFR) AF: 0.00830 AC: 345 AN: 41574

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000944 Hom.: 0

Bravo AF: 0.00251

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carpenter syndrome Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.62
PhyloP100		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs150762175; hg19: chr6-57059563;