6-57196617-ACAATCAATCAAT-ACAATCAATCAATCAAT

Variant names:

• chr6-57196617-A-ACAAT
• rs45542438
• NM_016277.5:c.242-15_242-12dupATTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_016277.5(RAB23):​c.242-15_242-12dupATTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,612,268 control chromosomes in the GnomAD database, including 20 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (20 hom.)
• Consequence: RAB23 NM_016277.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.26
• 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-57196617-A-ACAAT is Benign according to our data. Variant chr6-57196617-A-ACAAT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357645.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00362 (551/152296) while in subpopulation AMR AF = 0.00542 (83/15300). AF 95% confidence interval is 0.00487. There are 0 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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.242-15_242-12dupATTG		intron	N/A	NP_057361.3
	RAB23	NM_001278666.2		c.242-15_242-12dupATTG		intron	N/A	NP_001265595.1	Q9ULC3
	RAB23	NM_001278667.2		c.242-15_242-12dupATTG		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.242-12_242-11insATTG		intron	N/A	ENSP00000417610.1	Q9ULC3
	RAB23	ENST00000317483.4	TSL:1	c.242-12_242-11insATTG		intron	N/A	ENSP00000320413.3	Q9ULC3
	RAB23	ENST00000875526.1		c.242-12_242-11insATTG		intron	N/A	ENSP00000545585.1

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 551 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00331 AC: 808 AN: 244302 AF XY: 0.00342

Gnomad AFR exome AF: 0.000571

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00646

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00431

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00534 AC: 7802 AN: 1459972 Hom.: 20 Cov.: 31 AF XY: 0.00522 AC XY: 3792 AN XY: 726192

African (AFR) AF: 0.000958 AC: 32 AN: 33402

American (AMR) AF: 0.00292 AC: 130 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00621 AC: 162 AN: 26098

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39604

South Asian (SAS) AF: 0.00321 AC: 276 AN: 86082

European-Finnish (FIN) AF: 0.00188 AC: 100 AN: 53176

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00610 AC: 6780 AN: 1110994

Other (OTH) AF: 0.00507 AC: 306 AN: 60310

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74472

African (AFR) AF: 0.000938 AC: 39 AN: 41572

American (AMR) AF: 0.00542 AC: 83 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00168 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Carpenter syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45542438; hg19: chr6-57061415;