rs758143699
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_014141.6(CNTNAP2):āc.208G>Cā(p.Gly70Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. G70G) has been classified as Likely benign.
Frequency
Consequence
NM_014141.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTNAP2 | NM_014141.6 | c.208G>C | p.Gly70Arg | missense_variant, splice_region_variant | 2/24 | ENST00000361727.8 | |
CNTNAP2 | XM_017011950.3 | c.208G>C | p.Gly70Arg | missense_variant, splice_region_variant | 2/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTNAP2 | ENST00000361727.8 | c.208G>C | p.Gly70Arg | missense_variant, splice_region_variant | 2/24 | 1 | NM_014141.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250552Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135426
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1456950Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 725132
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cortical dysplasia-focal epilepsy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2017 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 205298). This variant is present in population databases (rs758143699, ExAC 0.009%). This sequence change replaces glycine with arginine at codon 70 of the CNTNAP2 protein (p.Gly70Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 2 of the CNTNAP2 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2013 | p.G70R:GGT>CGT: c.208G>C in CNTNAP2 gene (NM_014141.5). The Gly70Arg missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of an uncharged Glycine residue with a positively charged Arginine residue at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, there are no reported missense mutations associated with epilepsy in this region of the protein.The variant is found in CHILD-EPI panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at