1-10232333-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001365951.3(KIF1B):c.5C>T(p.Ser2Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,609,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S2S) has been classified as Likely benign.
Frequency
Consequence
NM_001365951.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KIF1B | NM_001365951.3 | c.5C>T | p.Ser2Leu | missense_variant | Exon 2 of 49 | ENST00000676179.1 | NP_001352880.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152016Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250604Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135388
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1457558Hom.: 0 Cov.: 29 AF XY: 0.0000152 AC XY: 11AN XY: 725296
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152016Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.S2L variant (also known as c.5C>T), located in coding exon 1 of the KIF1B gene, results from a C to T substitution at nucleotide position 5. The serine at codon 2 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in an individual with a clinical suspicion of Charcot Marie Tooth (Yalcintepe S et al. Turk Neurosurg, 2021;31:888-895). 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. -
Charcot-Marie-Tooth disease type 2 Uncertain:1
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2 of the KIF1B protein (p.Ser2Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 34169998). ClinVar contains an entry for this variant (Variation ID: 1444802). 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. -
KIF1B-related disorder Uncertain:1
The KIF1B c.5C>T variant is predicted to result in the amino acid substitution p.Ser2Leu. This variant was reported in an individual with clinical symptoms of Charcot-Marie-Tooth disease (in Table III in Yalcintepe et al 2021. PubMed ID: 34169998). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-10292391-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at