4-1212319-G-A

Variant names:

• chr4-1212319-G-A
• rs1372176539
• NM_001012614.2:c.1211C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001012614.2(CTBP1):​c.1211C>T​(p.Ala404Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000078 in 768,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: CTBP1 NM_001012614.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.19
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20387912).

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.1211C>T	p.Ala404Val	missense	Exon 10 of 10	NP_001012632.1	Q13363-2
	CTBP1	NM_001377186.1		c.1247C>T	p.Ala416Val	missense	Exon 9 of 9	NP_001364115.1
	CTBP1	NM_001328.3		c.1244C>T	p.Ala415Val	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.1211C>T	p.Ala404Val	missense	Exon 10 of 10	ENSP00000372411.3	Q13363-2
	CTBP1	ENST00000290921.10	TSL:1	c.1244C>T	p.Ala415Val	missense	Exon 9 of 9	ENSP00000290921.6	Q13363-1
	CTBP1-AS	ENST00000625256.1	TSL:1	n.792G>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.00000681 AC: 1 AN: 146750 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

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

GnomAD4 exome AF: 0.00000804 AC: 5 AN: 622012 Hom.: 0 Cov.: 20 AF XY: 0.00000618 AC XY: 2 AN XY: 323460

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12032

American (AMR) AF: 0.00 AC: 0 AN: 19580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13210

East Asian (EAS) AF: 0.00 AC: 0 AN: 17308

South Asian (SAS) AF: 0.0000167 AC: 1 AN: 60000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2978

European-Non Finnish (NFE) AF: 0.00000911 AC: 4 AN: 438924

Other (OTH) AF: 0.00 AC: 0 AN: 26306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000308402), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000681 AC: 1 AN: 146750 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 71560

African (AFR) AF: 0.00 AC: 0 AN: 40532

American (AMR) AF: 0.0000671 AC: 1 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4564

South Asian (SAS) AF: 0.00 AC: 0 AN: 4230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66470

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.34	N
PhyloP100		7.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.26
Sift	Benign	0.051	T
Sift4G	Benign	0.31	T
Polyphen		0.0030	B
Vest4		0.065
MutPred		0.13		Loss of glycosylation at P418 (P = 0.1153)
MVP		0.63
MPC		0.46
ClinPred		0.77	D
GERP RS		4.2
Varity_R		0.085
gMVP		0.49
Mutation Taster		=80/20	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: rs1372176539; hg19: chr4-1206107;