rs1231027223

Variant names:

• chr13-48499726-C-T
• rs1231027223
• NM_001268.4:c.1279G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001268.4(RCBTB2):​c.1279G>A​(p.Glu427Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RCBTB2 NM_001268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

Genes affected

RCBTB2 (HGNC:1914): (RCC1 and BTB domain containing protein 2) This gene encodes a protein containing two C-terminal BTB/POZ domains that is related to regulator of chromosome condensation (RCC). The encoded protein may act as a guanine nucleotide exchange factor. This gene is observed to be lost or underexpressed in prostate cancers. There is a pseudogene of this gene on chromosome 10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18796116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001268.4. 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
	RCBTB2	NM_001268.4	MANE Select	c.1279G>A	p.Glu427Lys	missense	Exon 13 of 15	NP_001259.1	O95199-1
	RCBTB2	NM_001286830.2		c.1294G>A	p.Glu432Lys	missense	Exon 12 of 14	NP_001273759.1	B4DWG0
	RCBTB2	NM_001352429.2		c.1291G>A	p.Glu431Lys	missense	Exon 10 of 12	NP_001339358.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCBTB2	ENST00000344532.8	TSL:1 MANE Select	c.1279G>A	p.Glu427Lys	missense	Exon 13 of 15	ENSP00000345144.3	O95199-1
	RCBTB2	ENST00000544904.3	TSL:1	c.1207G>A	p.Glu403Lys	missense	Exon 10 of 12	ENSP00000443904.2	O95199-2
	RCBTB2	ENST00000430805.6	TSL:2	c.1294G>A	p.Glu432Lys	missense	Exon 12 of 14	ENSP00000389910.2	B4DWG0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251472 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.098
Sift	Benign	0.091	T
Sift4G	Benign	0.29	T
Polyphen		0.24	B
Vest4		0.40
MutPred		0.47		Gain of ubiquitination at E432 (P = 0.0085)
MVP		0.69
MPC		0.20
ClinPred		0.74	D
GERP RS		3.5
Varity_R		0.054
gMVP		0.28
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1231027223; hg19: chr13-49073862;