NM_001268.4:c.1480G>A

Variant names:

• chr13-48496226-C-T
• rs753765212
• NM_001268.4:c.1480G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001268.4(RCBTB2):​c.1480G>A​(p.Ala494Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000695 in 1,583,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: RCBTB2 NM_001268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02843362).

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.1480G>A	p.Ala494Thr	missense	Exon 14 of 15	NP_001259.1	O95199-1
	RCBTB2	NM_001286830.2		c.1495G>A	p.Ala499Thr	missense	Exon 13 of 14	NP_001273759.1	B4DWG0
	RCBTB2	NM_001352429.2		c.1492G>A	p.Ala498Thr	missense	Exon 11 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.1480G>A	p.Ala494Thr	missense	Exon 14 of 15	ENSP00000345144.3	O95199-1
	RCBTB2	ENST00000544904.3	TSL:1	c.1408G>A	p.Ala470Thr	missense	Exon 11 of 12	ENSP00000443904.2	O95199-2
	RCBTB2	ENST00000430805.6	TSL:2	c.1495G>A	p.Ala499Thr	missense	Exon 13 of 14	ENSP00000389910.2	B4DWG0

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000141 AC: 33 AN: 234116 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000554

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000650 AC: 93 AN: 1431562 Hom.: 0 Cov.: 30 AF XY: 0.0000534 AC XY: 38 AN XY: 711590

African (AFR) AF: 0.0000311 AC: 1 AN: 32164

American (AMR) AF: 0.00 AC: 0 AN: 39802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.000788 AC: 30 AN: 38050

South Asian (SAS) AF: 0.00 AC: 0 AN: 82774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.0000420 AC: 46 AN: 1096380

Other (OTH) AF: 0.000272 AC: 16 AN: 58806

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152254 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74436

African (AFR) AF: 0.000120 AC: 5 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	0.097
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.67	N
PhyloP100		1.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.087
Sift	Benign	0.39	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.44		Gain of helix (P = 0.1736)
MVP		0.79
MPC		0.11
ClinPred		0.049	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.18
Mutation Taster		=94/6	polymorphism

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: rs753765212; hg19: chr13-49070362; COSMIC: COSV106061845; COSMIC: COSV106061845;