rs45479896

Variant names:

• chr6-57196547-A-C
• rs45479896
• NM_016277.5:c.301T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-57196547-A-C
• chr6-57196547-A-G
• chr6-57196547-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016277.5(RAB23):​c.301T>G​(p.Ser101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,614,042 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (54 hom.)
• Consequence: RAB23 NM_016277.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.20
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074023604).
• BP6: Variant 6-57196547-A-C is Benign according to our data. Variant chr6-57196547-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357644.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00582 (886/152316) while in subpopulation NFE AF = 0.00845 (575/68020). AF 95% confidence interval is 0.00788. There are 8 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.301T>G	p.Ser101Ala	missense	Exon 4 of 7	NP_057361.3
	RAB23	NM_001278666.2		c.301T>G	p.Ser101Ala	missense	Exon 4 of 7	NP_001265595.1	Q9ULC3
	RAB23	NM_001278667.2		c.301T>G	p.Ser101Ala	missense	Exon 4 of 7	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.301T>G	p.Ser101Ala	missense	Exon 4 of 7	ENSP00000417610.1	Q9ULC3
	RAB23	ENST00000317483.4	TSL:1	c.301T>G	p.Ser101Ala	missense	Exon 4 of 7	ENSP00000320413.3	Q9ULC3
	RAB23	ENST00000875526.1		c.301T>G	p.Ser101Ala	missense	Exon 4 of 7	ENSP00000545585.1

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152198 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00845

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00600 AC: 1507 AN: 251026 AF XY: 0.00601

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00876

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00701 AC: 10252 AN: 1461726 Hom.: 54 Cov.: 31 AF XY: 0.00694 AC XY: 5050 AN XY: 727168

African (AFR) AF: 0.000926 AC: 31 AN: 33476

American (AMR) AF: 0.00284 AC: 127 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39660

South Asian (SAS) AF: 0.00416 AC: 359 AN: 86252

European-Finnish (FIN) AF: 0.0111 AC: 592 AN: 53400

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.00780 AC: 8671 AN: 1111946

Other (OTH) AF: 0.00702 AC: 424 AN: 60378

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152316 Hom.: 8 Cov.: 32 AF XY: 0.00575 AC XY: 428 AN XY: 74484

African (AFR) AF: 0.00156 AC: 65 AN: 41586

American (AMR) AF: 0.00458 AC: 70 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00845 AC: 575 AN: 68020

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00764 Hom.: 20

Bravo AF: 0.00511

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00633 AC: 768

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.00971

EpiControl AF: 0.00848

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Carpenter syndrome (2)
-	-	2	RAB23-related Carpenter syndrome (2)
-	-	1	RAB23-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.14
Sift	Benign	0.58	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.72
MPC		0.15
ClinPred		0.0035	T
GERP RS		0.76
Varity_R		0.061
gMVP		0.22
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs45479896; hg19: chr6-57061345;