6-57187131-T-C

Position:

• chr6-57187131-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_016277.5(RAB23):​c.*3330A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,172 control chromosomes in the GnomAD database, including 1,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1637 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: RAB23 NM_016277.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.770

Genes affected

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: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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 6-57187131-T-C is Benign according to our data. Variant chr6-57187131-T-C is described in ClinVar as [Benign]. Clinvar id is 908519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG2	NM_004282.4	c.*2941T>C		3_prime_UTR_variant	3/3	ENST00000370693.5	NP_004273.1
RAB23	NM_016277.5	c.*3330A>G		3_prime_UTR_variant	7/7	ENST00000468148.6	NP_057361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG2	ENST00000370693.5	c.*2941T>C		3_prime_UTR_variant	3/3	1	NM_004282.4	ENSP00000359727	P1
RAB23	ENST00000468148.6	c.*3330A>G		3_prime_UTR_variant	7/7	1	NM_016277.5	ENSP00000417610	P1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21740 AN: 152054 Hom.: 1632 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.0430

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.150

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: 0.143 AC: 21759 AN: 152172 Hom.: 1637 Cov.: 32 AF XY: 0.142 AC XY: 10564 AN XY: 74386

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.0433

Gnomad4 SAS AF: 0.0466

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.148

Alfa AF: 0.147 Hom.: 218

Bravo AF: 0.142

Asia WGS AF: 0.0440 AC: 153 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RAB23-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Benign	0.86

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: rs72868608; hg19: chr6-57051929;