7-147120974-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_014141.6(CNTNAP2):c.755-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014141.6 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CNTNAP2 | NM_014141.6 | c.755-5C>T | splice_region_variant, intron_variant | ENST00000361727.8 | NP_054860.1 | |||
CNTNAP2 | XM_017011950.3 | c.755-5C>T | splice_region_variant, intron_variant | XP_016867439.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CNTNAP2 | ENST00000361727.8 | c.755-5C>T | splice_region_variant, intron_variant | 1 | NM_014141.6 | ENSP00000354778.3 |
Frequencies
GnomAD3 genomes AF: 0.000315 AC: 48AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000267 AC: 67AN: 251082Hom.: 0 AF XY: 0.000265 AC XY: 36AN XY: 135706
GnomAD4 exome AF: 0.000153 AC: 223AN: 1460844Hom.: 0 Cov.: 30 AF XY: 0.000144 AC XY: 105AN XY: 726748
GnomAD4 genome AF: 0.000322 AC: 49AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74472
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 30, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: CNTNAP2 c.755-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CNTNAP2 causing Pitt-Hopkins-Like Syndrome 1 (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.755-5C>T has been reported in the literature in an individual affected with Rolandic epilepsy (Bobbili_2018). This report does not provide unequivocal conclusions about association of the variant with Pitt-Hopkins-Like Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29358611). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including uncertain significance (n=4), pathogenic (n=1) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 22, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 24, 2017 | - - |
Childhood epilepsy with centrotemporal spikes Pathogenic:1
Pathogenic, no assertion criteria provided | case-control | Bioinformatics Core, Luxembourg Center for Systems Biomedicine | Jan 01, 2017 | CAADphred>15 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2017 | The c.755-5C>T intronic variant results from a C to T substitution 5 nucleotides upstream from exon 6 in the CNTNAP2 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Autism, susceptibility to, 15;C2750246:Cortical dysplasia-focal epilepsy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | CNTNAP2 NM_014141.5 exon 6 c.755-5C>T: This variant has not been reported in the literature but is present in 23/126370 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs369675346). This variant is present in ClinVar (Variation ID:136809). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Cortical dysplasia-focal epilepsy syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at