13-48499627-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001268.4(RCBTB2):​c.1378G>A​(p.Ala460Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RCBTB2
NM_001268.4 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.47
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RCBTB2NM_001268.4 linkc.1378G>A p.Ala460Thr missense_variant Exon 13 of 15 ENST00000344532.8 NP_001259.1 O95199-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RCBTB2ENST00000344532.8 linkc.1378G>A p.Ala460Thr missense_variant Exon 13 of 15 1 NM_001268.4 ENSP00000345144.3 O95199-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 30, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1378G>A (p.A460T) alteration is located in exon 13 (coding exon 10) of the RCBTB2 gene. This alteration results from a G to A substitution at nucleotide position 1378, causing the alanine (A) at amino acid position 460 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;T;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.66
D;D;D;D
MetaSVM
Uncertain
-0.095
T
MutationAssessor
Uncertain
2.6
M;.;.;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.0
N;N;N;.
REVEL
Uncertain
0.44
Sift
Benign
0.14
T;T;T;.
Sift4G
Uncertain
0.022
D;D;D;D
Polyphen
0.24
B;D;B;.
Vest4
0.76
MutPred
0.46
.;.;Gain of phosphorylation at A465 (P = 0.0378);.;
MVP
0.85
MPC
0.24
ClinPred
0.96
D
GERP RS
5.1
Varity_R
0.31
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.21
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1566266741; hg19: chr13-49073763; API