rs869025316
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001371986.1(UNC80):c.5296C>T(p.Pro1766Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,551,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001371986.1 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
UNC80 | NM_001371986.1 | c.5296C>T | p.Pro1766Ser | missense_variant | Exon 33 of 65 | ENST00000673920.1 | NP_001358915.1 | |
UNC80 | NM_032504.2 | c.5098C>T | p.Pro1700Ser | missense_variant | Exon 32 of 64 | NP_115893.1 | ||
UNC80 | NM_182587.4 | c.5083C>T | p.Pro1695Ser | missense_variant | Exon 32 of 63 | NP_872393.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
UNC80 | ENST00000673920.1 | c.5296C>T | p.Pro1766Ser | missense_variant | Exon 33 of 65 | NM_001371986.1 | ENSP00000501211.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000380 AC: 6AN: 157842Hom.: 0 AF XY: 0.0000360 AC XY: 3AN XY: 83352
GnomAD4 exome AF: 0.0000243 AC: 34AN: 1399692Hom.: 0 Cov.: 31 AF XY: 0.0000174 AC XY: 12AN XY: 690338
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 Pathogenic:2
- -
- -
not provided Uncertain:2
Published functional studies suggest this variant has a damaging effect on NALCN channel currents (Stray-Pedersen et al., 2016); 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: 26708751, 31589614) -
Experimental studies have shown that this missense change affects UNC80 function (PMID: 26708751). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UNC80 protein function. ClinVar contains an entry for this variant (Variation ID: 222010). This missense change has been observed in individual(s) with UNC80-related conditions (PMID: 26708751). This variant is present in population databases (no rsID available, gnomAD 0.05%). This sequence change replaces proline with serine at codon 1700 of the UNC80 protein (p.Pro1700Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. 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
Variant summary: UNC80 c.5098C>T (p.Pro1700Ser) results in a non-conservative amino acid change located in the Protein UNC80, central region (IPR045852) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 157842 control chromosomes. c.5098C>T has been reported in the literature in at-least one individual affected with persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability (example: Stray-Pedersen_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a damaging effect on NALCN channel currents (Stray-Pedersen _2016). The following publication has been ascertained in the context of this evaluation (PMID: 26708751). ClinVar contains an entry for this variant (Variation ID: 222010). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at