Genetic Variant NM_001268.4:c.1259G>C (chr13-48499746-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001268.4(RCBTB2):c.1259G>C(p.Arg420Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R420C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RCBTB2
NM_001268.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.47

Publications

0 publications found

Variant links:

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]

RCBTB2 links:

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

RB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RCBTB2	NM_001268.4	MANE Select	c.1259G>C	p.Arg420Pro	missense	Exon 13 of 15	NP_001259.1	O95199-1
RCBTB2	NM_001286830.2		c.1274G>C	p.Arg425Pro	missense	Exon 12 of 14	NP_001273759.1	B4DWG0
RCBTB2	NM_001352429.2		c.1271G>C	p.Arg424Pro	missense	Exon 10 of 12	NP_001339358.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RCBTB2	ENST00000344532.8	TSL:1 MANE Select	c.1259G>C	p.Arg420Pro	missense	Exon 13 of 15	ENSP00000345144.3	O95199-1
RCBTB2	ENST00000544904.3	TSL:1	c.1187G>C	p.Arg396Pro	missense	Exon 10 of 12	ENSP00000443904.2	O95199-2
RCBTB2	ENST00000430805.6	TSL:2	c.1274G>C	p.Arg425Pro	missense	Exon 12 of 14	ENSP00000389910.2	B4DWG0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.4

PhyloP100

7.5

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.97

Vest4

0.96

MutPred

0.74

Gain of glycosylation at S427 (P = 0.0349)

MVP

0.97

MPC

0.41

ClinPred

1.0

GERP RS

5.2

Varity_R

0.95

gMVP

0.88

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over