rs3012075

chr10-125026397-A-Gchr10-125026397-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022802.3(CTBP2):c.1363T>C(p.Tyr455His) variant causes a missense change. The variant allele was found at a frequency of 0.481 in 1,609,638 control chromosomes in the GnomAD database, including 189,586 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15791 hom., cov: 32)
  • Exomes 𝑓: 0.48 (173795 hom.)
• Consequence: CTBP2 NM_022802.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.95

Genes affected

CTBP2 (HGNC:2495): (C-terminal binding protein 2) This gene produces alternative transcripts encoding two distinct proteins. One protein is a transcriptional repressor, while the other isoform is a major component of specialized synapses known as synaptic ribbons. Both proteins contain a NAD+ binding domain similar to NAD+-dependent 2-hydroxyacid dehydrogenases. A portion of the 3' untranslated region was used to map this gene to chromosome 21q21.3; however, it was noted that similar loci elsewhere in the genome are likely. Blast analysis shows that this gene is present on chromosome 10. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5206962E-5).
• BP6: Variant 10-125026397-A-G is Benign according to our data. Variant chr10-125026397-A-G is described in ClinVar as [Benign]. Clinvar id is 3059822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTBP2	NM_022802.3	c.1363T>C	p.Tyr455His	missense_variant	1/9	ENST00000309035.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTBP2	ENST00000309035.11	c.1363T>C	p.Tyr455His	missense_variant	1/9	1	NM_022802.3

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67639 AN: 151694 Hom.: 15788 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.435

GnomAD3 exomes AF: 0.472 AC: 115693 AN: 244920 Hom.: 28455 AF XY: 0.478 AC XY: 63470 AN XY: 132832

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.451

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.485 AC: 706848 AN: 1457826 Hom.: 173795 Cov.: 68 AF XY: 0.485 AC XY: 351357 AN XY: 724408

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.334

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.585

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.564

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.446 AC: 67677 AN: 151812 Hom.: 15791 Cov.: 32 AF XY: 0.449 AC XY: 33284 AN XY: 74200

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.627

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.439

Alfa AF: 0.480 Hom.: 26331

Bravo AF: 0.423

TwinsUK AF: 0.486 AC: 1801

ALSPAC AF: 0.482 AC: 1859

ESP6500AA AF: 0.329 AC: 1449

ESP6500EA AF: 0.497 AC: 4276

ExAC AF: 0.474 AC: 57527

Asia WGS AF: 0.555 AC: 1932 AN: 3478

EpiCase AF: 0.492

EpiControl AF: 0.484

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CTBP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.21
Sift	Benign	0.031	D
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.11
MPC		0.13
ClinPred		0.024	T
GERP RS		4.0
gMVP		0.36

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: rs3012075; hg19: chr10-126714966; COSMIC: COSV58338964;