6-57210429-G-C

Variant names:

• chr6-57210429-G-C
• rs45474592
• NM_016277.5:c.-49C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016277.5(RAB23):​c.-49C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RAB23 NM_016277.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.483
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB23	NM_016277.5	MANE Select	c.-49C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_057361.3
	RAB23	NM_016277.5	MANE Select	c.-49C>G		5_prime_UTR	Exon 2 of 7	NP_057361.3
	RAB23	NM_001278666.2		c.-49C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001265595.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB23	ENST00000468148.6	TSL:1 MANE Select	c.-49C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000417610.1
	RAB23	ENST00000317483.4	TSL:1	c.-49C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000320413.3
	RAB23	ENST00000468148.6	TSL:1 MANE Select	c.-49C>G		5_prime_UTR	Exon 2 of 7	ENSP00000417610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405318 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 702516

African (AFR) AF: 0.00 AC: 0 AN: 32244

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 85010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061680

Other (OTH) AF: 0.00 AC: 0 AN: 58508

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.7
DANN	Benign	0.65
PhyloP100		0.48

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: rs45474592; hg19: chr6-57075227;