rs148453565
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_014141.6(CNTNAP2):c.2123T>C(p.Val708Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V708F) has been classified as Uncertain significance.
Frequency
Consequence
NM_014141.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTNAP2 | NM_014141.6 | c.2123T>C | p.Val708Ala | missense_variant | 14/24 | ENST00000361727.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTNAP2 | ENST00000361727.8 | c.2123T>C | p.Val708Ala | missense_variant | 14/24 | 1 | NM_014141.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00142 AC: 216AN: 152050Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000391 AC: 98AN: 250820Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135624
GnomAD4 exome AF: 0.000148 AC: 217AN: 1461844Hom.: 0 Cov.: 33 AF XY: 0.000127 AC XY: 92AN XY: 727220
GnomAD4 genome ? AF: 0.00142 AC: 216AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00134 AC XY: 100AN XY: 74398
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 08, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2024 | Variant summary: CNTNAP2 c.2123T>C (p.Val708Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 250820 control chromosomes. c.2123T>C has been reported in the literature in at-least one individual affected with Autism, however insufficient information was provided for further analysis (example, Murdoch_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Autism, Susceptibility To, 15. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25621974). ClinVar contains an entry for this variant (Variation ID: 205256). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 02, 2015 | - - |
Autism, susceptibility to, 15;C2750246:Cortical dysplasia-focal epilepsy syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | May 16, 2021 | CNTNAP2 NM_014141.5 exon 14 p.Val708Ala (c.2123T>C): This variant has not been reported in the literature but is present in 0.4% (200/41378) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-147903589-T-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:205256). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2020 | Observed as a rare heterozygous missense variant in a population of individuals with autism spectrum disorder; however, the authors found no significant association with autism risk (Murdoch et al., 2015); This variant is associated with the following publications: (PMID: 25621974) - |
Cortical dysplasia-focal epilepsy syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
CNTNAP2-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 20, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at