Genetic Variant CTBP2:p.Gly117Arg (chr10-125002969-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001329.4(CTBP2):c.349G>C(p.Gly117Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G117S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

CTBP2
NM_001329.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

Publications

7 publications found

Variant links:

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]

CTBP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-125002969-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1696855.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTBP2	NM_001329.4	MANE Select	c.349G>C	p.Gly117Arg	missense	Exon 5 of 11	NP_001320.1	P56545-1
CTBP2	NM_022802.3		c.1969G>C	p.Gly657Arg	missense	Exon 3 of 9	NP_073713.2	P56545-2
CTBP2	NM_001363508.2		c.553G>C	p.Gly185Arg	missense	Exon 3 of 9	NP_001350437.1	P56545-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTBP2	ENST00000337195.11	TSL:1 MANE Select	c.349G>C	p.Gly117Arg	missense	Exon 5 of 11	ENSP00000338615.5	P56545-1
CTBP2	ENST00000309035.11	TSL:1	c.1969G>C	p.Gly657Arg	missense	Exon 3 of 9	ENSP00000311825.6	P56545-2
CTBP2	ENST00000334808.10	TSL:1	c.553G>C	p.Gly185Arg	missense	Exon 3 of 9	ENSP00000357816.5	P56545-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.063

MutationAssessor

Benign

-0.83

PhyloP100

6.2

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.63

Sift

Benign

0.15

Sift4G

Benign

0.56

Polyphen

0.46

Vest4

0.76

MutPred

0.44

Loss of catalytic residue at A184 (P = 0.039)

MVP

0.84

MPC

1.7

ClinPred

0.98

GERP RS

3.8

Varity_R

0.94

gMVP

0.91

Mutation Taster

=25/75

disease causing

(source)

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

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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