2-50538612-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_001330078.2(NRXN1):c.1784G>A(p.Arg595His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000801 in 1,498,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R595C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001330078.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151982Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000171 AC: 3AN: 175082Hom.: 0 AF XY: 0.0000325 AC XY: 3AN XY: 92366
GnomAD4 exome AF: 0.00000817 AC: 11AN: 1346722Hom.: 0 Cov.: 31 AF XY: 0.00000913 AC XY: 6AN XY: 656998
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151982Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74208
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1904G>A (p.R635H) alteration is located in exon 11 (coding exon 10) of the NRXN1 gene. This alteration results from a G to A substitution at nucleotide position 1904, causing the arginine (R) at amino acid position 635 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
A variant of uncertain significance has been identified in the NRXN1 gene. The R635H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R635H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the R635H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Pitt-Hopkins-like syndrome 2 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 635 of the NRXN1 protein (p.Arg635His). This variant is present in population databases (rs761279630, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423467). 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. -
Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at