rs45459199

Variant names:

• chr6-57193814-C-T
• rs45459199
• NM_016277.5:c.574+28G>A

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.574+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00895 in 1,609,212 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (110 hom.)
• Consequence: RAB23 NM_016277.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.519
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.79).
• BP6: Variant 6-57193814-C-T is Benign according to our data. Variant chr6-57193814-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1201159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00965 (1468/152166) while in subpopulation NFE AF = 0.0119 (812/67968). AF 95% confidence interval is 0.0113. There are 22 homozygotes in GnomAd4. There are 823 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016277.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB23	NM_016277.5	MANE Select	c.574+28G>A		intron	N/A	NP_057361.3
	RAB23	NM_001278666.2		c.574+28G>A		intron	N/A	NP_001265595.1	Q9ULC3
	RAB23	NM_001278667.2		c.574+28G>A		intron	N/A	NP_001265596.1	Q9ULC3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB23	ENST00000468148.6	TSL:1 MANE Select	c.574+28G>A		intron	N/A	ENSP00000417610.1	Q9ULC3
	RAB23	ENST00000317483.4	TSL:1	c.574+28G>A		intron	N/A	ENSP00000320413.3	Q9ULC3
	RAB23	ENST00000875526.1		c.574+28G>A		intron	N/A	ENSP00000545585.1

Frequencies

GnomAD3 genomes AF: 0.00965 AC: 1468 AN: 152050 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00673

GnomAD2 exomes AF: 0.0100 AC: 2470 AN: 247004 AF XY: 0.00998

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0422

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00747

GnomAD4 exome AF: 0.00888 AC: 12939 AN: 1457046 Hom.: 110 Cov.: 30 AF XY: 0.00877 AC XY: 6353 AN XY: 724510

African (AFR) AF: 0.000719 AC: 24 AN: 33370

American (AMR) AF: 0.00273 AC: 121 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.000400 AC: 34 AN: 85000

European-Finnish (FIN) AF: 0.0379 AC: 2015 AN: 53218

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5744

European-Non Finnish (NFE) AF: 0.00902 AC: 10007 AN: 1109794

Other (OTH) AF: 0.00741 AC: 446 AN: 60156

GnomAD4 genome AF: 0.00965 AC: 1468 AN: 152166 Hom.: 22 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74380

African (AFR) AF: 0.00111 AC: 46 AN: 41528

American (AMR) AF: 0.00406 AC: 62 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0463 AC: 490 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 812 AN: 67968

Other (OTH) AF: 0.00666 AC: 14 AN: 2102

Alfa AF: 0.0116 Hom.: 5

Bravo AF: 0.00587

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.55
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs45459199; hg19: chr6-57058612;