rs147447659
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_014141.6(CNTNAP2):c.1879G>A(p.Val627Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. V627A) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNTNAP2 | NM_014141.6 | c.1879G>A | p.Val627Ile | missense_variant | 12/24 | ENST00000361727.8 | |
CNTNAP2 | XM_017011950.3 | c.1879G>A | p.Val627Ile | missense_variant | 12/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNTNAP2 | ENST00000361727.8 | c.1879G>A | p.Val627Ile | missense_variant | 12/24 | 1 | NM_014141.6 | P1 | |
CNTNAP2 | ENST00000636870.1 | n.1741G>A | non_coding_transcript_exon_variant | 10/22 | 5 | ||||
CNTNAP2 | ENST00000637825.1 | n.1362G>A | non_coding_transcript_exon_variant | 9/14 | 5 | ||||
CNTNAP2 | ENST00000638117.1 | n.1782G>A | non_coding_transcript_exon_variant | 11/13 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000250 AC: 38AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251298Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135816
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461682Hom.: 1 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 727170
GnomAD4 genome ? AF: 0.000250 AC: 38AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74464
ClinVar
Submissions by phenotype
Cortical dysplasia-focal epilepsy syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 29, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 627 of the CNTNAP2 protein (p.Val627Ile). This variant is present in population databases (rs147447659, gnomAD 0.05%). This missense change has been observed in individual(s) with specific language impairment (PMID: 24807205). ClinVar contains an entry for this variant (Variation ID: 205251). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 23, 2022 | Variant summary: CNTNAP2 c.1879G>A (p.Val627Ile) results in a conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 282700 control chromosomes (gnomAD), predominantly at a frequency of 0.00048 within the African or African-American subpopulation in the gnomAD database. c.1879G>A has been reported in the literature in at least one individual affected with stuttering (Han_2014). This report does not provide unequivocal conclusions about association of the variant with Autism, Susceptibility 15. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. 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 | Jun 23, 2021 | The c.1879G>A (p.V627I) alteration is located in exon 12 (coding exon 12) of the CNTNAP2 gene. This alteration results from a G to A substitution at nucleotide position 1879, causing the valine (V) at amino acid position 627 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2021 | Observed in an individual with persistent developmental stuttering; however, additional information regarding the phenotype of the individual and information about parental testing were not provided and the authors concluded that CNTNAP2 variants were not associated with stuttering (Han et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24807205) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at