rs139694086
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_014141.6(CNTNAP2):āc.400T>Gā(p.Trp134Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000254 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W134L) has been classified as Uncertain significance.
Frequency
Consequence
NM_014141.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTNAP2 | NM_014141.6 | c.400T>G | p.Trp134Gly | missense_variant, splice_region_variant | 3/24 | ENST00000361727.8 | |
CNTNAP2 | XM_017011950.3 | c.400T>G | p.Trp134Gly | missense_variant, splice_region_variant | 3/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTNAP2 | ENST00000361727.8 | c.400T>G | p.Trp134Gly | missense_variant, splice_region_variant | 3/24 | 1 | NM_014141.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251144Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135750
GnomAD4 exome AF: 0.000260 AC: 380AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.000276 AC XY: 201AN XY: 727198
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74348
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 15, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 12, 2023 | PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2024 | Reported previously in the compound heterozygous state in a patient with multifocal epilepsy, moderate intellectual disability, autism spectrum disorder, ADHD, language impairment, and neuroimaging abnormalities; this patient also harbored variants in other genes (PMID: 37183190); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37183190) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2018 | - - |
Cortical dysplasia-focal epilepsy syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | research | St. Anna Children's Cancer Research Institute (CCRI) | Feb 08, 2023 | ACMG classification of pathogenicity variant 1: PM2, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 134 of the CNTNAP2 protein (p.Trp134Gly). This variant is present in population databases (rs139694086, gnomAD 0.1%). This missense change has been observed in individual(s) with Pitt-Hopkins-like syndrome (PMID: 37183190). ClinVar contains an entry for this variant (Variation ID: 205321). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2021 | The c.400T>G (p.W134G) alteration is located in exon 3 (coding exon 3) of the CNTNAP2 gene. This alteration results from a T to G substitution at nucleotide position 400, causing the tryptophan (W) at amino acid position 134 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at