NM_001012614.2:c.1225G>A

Variant names:

• chr4-1212305-C-T
• rs1344128525
• NM_001012614.2:c.1225G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001012614.2(CTBP1):​c.1225G>A​(p.Ala409Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 541,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A409S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: CTBP1 NM_001012614.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23609981).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012614.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTBP1	NM_001012614.2	MANE Select	c.1225G>A	p.Ala409Thr	missense	Exon 10 of 10	NP_001012632.1	Q13363-2
	CTBP1	NM_001377186.1		c.1261G>A	p.Ala421Thr	missense	Exon 9 of 9	NP_001364115.1
	CTBP1	NM_001328.3		c.1258G>A	p.Ala420Thr	missense	Exon 9 of 9	NP_001319.1	X5D8Y5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTBP1	ENST00000382952.8	TSL:1 MANE Select	c.1225G>A	p.Ala409Thr	missense	Exon 10 of 10	ENSP00000372411.3	Q13363-2
	CTBP1	ENST00000290921.10	TSL:1	c.1258G>A	p.Ala420Thr	missense	Exon 9 of 9	ENSP00000290921.6	Q13363-1
	CTBP1-AS	ENST00000625256.1	TSL:1	n.778C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.00000723 AC: 1 AN: 138230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000259

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000152 AC: 2 AN: 131682 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000133

Gnomad FIN exome AF: 0.0000659

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 21 AN: 403462 Hom.: 0 Cov.: 10 AF XY: 0.0000467 AC XY: 10 AN XY: 214048

African (AFR) AF: 0.00 AC: 0 AN: 7280

American (AMR) AF: 0.00 AC: 0 AN: 17242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8974

East Asian (EAS) AF: 0.00 AC: 0 AN: 6882

South Asian (SAS) AF: 0.0000366 AC: 2 AN: 54660

European-Finnish (FIN) AF: 0.0000371 AC: 1 AN: 26982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2358

European-Non Finnish (NFE) AF: 0.0000684 AC: 18 AN: 263100

Other (OTH) AF: 0.00 AC: 0 AN: 15984

GnomAD4 genome AF: 0.00000723 AC: 1 AN: 138230 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 66840

African (AFR) AF: 0.0000259 AC: 1 AN: 38674

American (AMR) AF: 0.00 AC: 0 AN: 14040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3272

East Asian (EAS) AF: 0.00 AC: 0 AN: 3944

South Asian (SAS) AF: 0.00 AC: 0 AN: 3702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63246

Other (OTH) AF: 0.00 AC: 0 AN: 1934

Alfa AF: 0.0000291 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.36
Sift	Benign	0.24	T
Sift4G	Benign	0.48	T
Polyphen		0.14	B
Vest4		0.23
MutPred		0.11		Gain of glycosylation at A420 (P = 9e-04)
MVP		0.62
MPC		0.46
ClinPred		0.36	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.52
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1344128525; hg19: chr4-1206093;