13-48496198-T-A

Variant names:

• chr13-48496198-T-A
• rs1207958519
• NM_001268.4:c.1508A>T

Variant summary

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

The NM_001268.4(RCBTB2):​c.1508A>T​(p.Asp503Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D503N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RCBTB2 NM_001268.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1508A>T	p.Asp503Val	missense	Exon 14 of 15	NP_001259.1	O95199-1
	RCBTB2	NM_001286830.2		c.1523A>T	p.Asp508Val	missense	Exon 13 of 14	NP_001273759.1	B4DWG0
	RCBTB2	NM_001352429.2		c.1520A>T	p.Asp507Val	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.1508A>T	p.Asp503Val	missense	Exon 14 of 15	ENSP00000345144.3	O95199-1
	RCBTB2	ENST00000544904.3	TSL:1	c.1436A>T	p.Asp479Val	missense	Exon 11 of 12	ENSP00000443904.2	O95199-2
	RCBTB2	ENST00000430805.6	TSL:2	c.1523A>T	p.Asp508Val	missense	Exon 13 of 14	ENSP00000389910.2	B4DWG0

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.015
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.38
Sift	Benign	0.098	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.50
MutPred		0.52		Gain of ubiquitination at K506 (P = 0.1117)
MVP		0.87
MPC		0.30
ClinPred		0.76	D
GERP RS		5.0
Varity_R		0.40
gMVP		0.58
Mutation Taster		=67/33	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: rs1207958519; hg19: chr13-49070334;