rs182662

Positions:

• chr6-57189210-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_016277.5(RAB23):​c.*1251G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 152,198 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (29 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: RAB23 NM_016277.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.940

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]

BAG2 (HGNC:938): (BAG cochaperone 2) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The predicted BAG2 protein contains 211 amino acids. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

RAB23 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2673/152198) while in subpopulation NFE AF= 0.0264 (1792/67990). AF 95% confidence interval is 0.0253. There are 29 homozygotes in gnomad4. There are 1264 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB23	NM_016277.5	c.*1251G>A		3_prime_UTR_variant	7/7	ENST00000468148.6	NP_057361.3
BAG2	NM_004282.4	c.*5020C>T		3_prime_UTR_variant	3/3	ENST00000370693.5	NP_004273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148	c.*1251G>A		3_prime_UTR_variant	7/7	1	NM_016277.5	ENSP00000417610.1
BAG2	ENST00000370693.5	c.*5020C>T		3_prime_UTR_variant	3/3	1	NM_004282.4	ENSP00000359727.4
RAB23	ENST00000317483	c.*1251G>A		3_prime_UTR_variant	7/7	1		ENSP00000320413.3

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2672 AN: 152080 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0206

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0176 AC: 2673 AN: 152198 Hom.: 29 Cov.: 32 AF XY: 0.0170 AC XY: 1264 AN XY: 74428

Gnomad4 AFR AF: 0.00417

Gnomad4 AMR AF: 0.0208

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0247 Hom.: 17

Bravo AF: 0.0170

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carpenter syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.99
DANN	Benign	0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs182662; hg19: chr6-57054008;