chr4-1212284-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001012614.2(CTBP1):​c.1246G>A​(p.Val416Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,008,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

CTBP1
NM_001012614.2 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.53
Variant links:
Genes affected
CTBP1 (HGNC:2494): (C-terminal binding protein 1) This gene encodes a protein that binds to the C-terminus of adenovirus E1A proteins. This phosphoprotein is a transcriptional repressor and may play a role during cellular proliferation. This protein and the product of a second closely related gene, CTBP2, can dimerize. Both proteins can also interact with a polycomb group protein complex which participates in regulation of gene expression during development. Alternative splicing of transcripts from this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]
CTBP1-AS (HGNC:48337): (CTBP1 antisense RNA)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.073963225).
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTBP1NM_001012614.2 linkc.1246G>A p.Val416Ile missense_variant Exon 10 of 10 ENST00000382952.8 NP_001012632.1 Q13363-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTBP1ENST00000382952.8 linkc.1246G>A p.Val416Ile missense_variant Exon 10 of 10 1 NM_001012614.2 ENSP00000372411.3 Q13363-2

Frequencies

GnomAD3 genomes
AF:
0.0000787
AC:
11
AN:
139784
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000256
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000698
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000253
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000125
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000852
AC:
74
AN:
868378
Hom.:
0
Cov.:
36
AF XY:
0.0000695
AC XY:
30
AN XY:
431820
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000170
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00159
Gnomad4 SAS exome
AF:
0.0000292
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000726
Gnomad4 OTH exome
AF:
0.0000635
GnomAD4 genome
AF:
0.0000787
AC:
11
AN:
139784
Hom.:
0
Cov.:
32
AF XY:
0.0000739
AC XY:
5
AN XY:
67614
show subpopulations
Gnomad4 AFR
AF:
0.0000256
Gnomad4 AMR
AF:
0.0000698
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000253
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000125
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000473
Hom.:
0
ExAC
AF:
0.0000168
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Aug 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 427 of the CTBP1 protein (p.Val427Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CTBP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2440596). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome Uncertain:1
Oct 02, 2020
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
25
DANN
Benign
0.93
DEOGEN2
Benign
0.35
.;T
Eigen
Benign
-0.99
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.44
N
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.074
T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.0
.;N
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-0.28
N;N
REVEL
Benign
0.26
Sift
Benign
0.37
T;T
Sift4G
Benign
0.44
T;T
Polyphen
0.0050
.;B
Vest4
0.18
MutPred
0.090
.;Loss of methylation at K428 (P = 0.114);
MVP
0.29
MPC
0.38
ClinPred
0.025
T
GERP RS
0.94
Varity_R
0.034
gMVP
0.24

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs748609943; hg19: chr4-1206072; COSMIC: COSV99337591; COSMIC: COSV99337591; API