rs751491210
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014141.6(CNTNAP2):c.3577G>A(p.Ala1193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1193S) has been classified as Uncertain significance.
Frequency
Consequence
NM_014141.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTNAP2 | NM_014141.6 | c.3577G>A | p.Ala1193Thr | missense_variant | 22/24 | ENST00000361727.8 | |
LOC105375554 | XR_928093.3 | n.446-2080C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTNAP2 | ENST00000361727.8 | c.3577G>A | p.Ala1193Thr | missense_variant | 22/24 | 1 | NM_014141.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251462Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135914
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24AN XY: 727248
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74328
ClinVar
Submissions by phenotype
Cortical dysplasia-focal epilepsy syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 28, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1193 of the CNTNAP2 protein (p.Ala1193Thr). This variant is present in population databases (rs751491210, gnomAD 0.01%). This missense change has been observed in individual(s) with rolandic epilepsy (PMID: 29358611). This variant is also known as 148080842. ClinVar contains an entry for this variant (Variation ID: 433107). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 11, 2020 | - - |
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 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2024 | Variant summary: CNTNAP2 c.3577G>A (p.Ala1193Thr) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3577G>A has been reported in the literature in individuals affected with focal epilepsy (Bobbili_2018). These report(s) do 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). ClinVar contains an entry for this variant (Variation ID: 433107). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2020 | The p.A1193T variant (also known as c.3577G>A), located in coding exon 22 of the CNTNAP2 gene, results from a G to A substitution at nucleotide position 3577. The alanine at codon 1193 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at