2-240785051-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP2
The NM_001244008.2(KIF1A):c.658G>A(p.Val220Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V220F) has been classified as Pathogenic.
Frequency
Consequence
NM_001244008.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.658G>A | p.Val220Ile | missense_variant | 7/49 | ENST00000498729.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.658G>A | p.Val220Ile | missense_variant | 7/49 | 5 | NM_001244008.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152224Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249980Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135370
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461198Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726898
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152342Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74490
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2020 | The p.V220I variant (also known as c.658G>A), located in coding exon 6 of the KIF1A gene, results from a G to A substitution at nucleotide position 658. The valine at codon 220 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2022 | Reported as a polymorphism in published literature as it was identified in healthy controls (Esmaeeli Nieh et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26125038, 21820098, 21376300) - |
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 28, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 220 of the KIF1A protein (p.Val220Ile). This variant is present in population databases (rs201314877, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532858). 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 expected to disrupt KIF1A protein function. Experimental studies have shown that this missense change does not substantially affect KIF1A function (PMID: 26125038). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at