16-67611443-CAAAG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006565.4(CTCF):c.615_618delGAAA(p.Lys206ProfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006565.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome Pathogenic:4
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Criteria applied: PVS1,PS2_VSTR,PS4_MOD,PM2_SUP -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with CTCF-related neurodevelopmental disorder (MIM#615502). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four probands, including proven de novo events; and classified as pathogenic by a diagnostic laboratory in ClinVar (DECIPHER; PMID: 30893510, 31239556) (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
The heterozygous c.615_618del variant in CTCF has previously been reported in multiple individuals affected with CTCF-related intellectual developmental disorder [PMID:31239556,30893510] and it has been deposited in ClinVar as Pathogenic [ClinVar ID: 521287]. The c.615_618del variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.615_618del variant in CTCF is located in exon 3 of this 12-exon gene, predicted to incorporate a premature translation termination codon [p.(Lys206ProfsTer15)], and is expected to result in loss-of-function via nonsense mediated mRNA decay. Multiple loss-of-function variants that are downstream to the c.615_618del variant have been reported in the literature [PMID: 31239556] and ClinVar [ClinVar ID: 625526] in individuals with CTCF-related disorder. Based on available evidence this de novo c.615_618del p.(Lys206ProfsTer15) variant identified in CTCF gene is classified as Pathogenic -
Inborn genetic diseases Pathogenic:1
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not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36454652, 31239556, 28619046, 30893510) -
Intellectual disability Pathogenic:1
PVS1,PS2,PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at