chr4-1212284-C-T

Variant names:

• chr4-1212284-C-T
• rs748609943
• NM_001012614.2:c.1246G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.53

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)

ACMG classification

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
CTBP1	NM_001012614.2	c.1246G>A	p.Val416Ile	missense_variant	Exon 10 of 10	ENST00000382952.8	NP_001012632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTBP1	ENST00000382952.8	c.1246G>A	p.Val416Ile	missense_variant	Exon 10 of 10	1	NM_001012614.2	ENSP00000372411.3

Frequencies

GnomAD3 genomes AF: 0.0000787 AC: 11 AN: 139784 Hom.: 0 Cov.: 32

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

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

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

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

Other links and lift over

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