chr2-240719065-C-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1
The NM_001244008.2(KIF1A):c.5155G>A(p.Val1719Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
KIF1A
NM_001244008.2 missense
NM_001244008.2 missense
Scores
5
9
Clinical Significance
Conservation
PhyloP100: 1.59
Genes affected
KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP2
Missense variant where missense usually causes diseases, KIF1A
BP4
Computational evidence support a benign effect (MetaRNN=0.036414057).
BP6
Variant 2-240719065-C-T is Benign according to our data. Variant chr2-240719065-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464259.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000105 (154/1460118) while in subpopulation AMR AF= 0.00163 (73/44652). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4_exome. There are 77 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.5155G>A | p.Val1719Met | missense_variant | 47/49 | ENST00000498729.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.5155G>A | p.Val1719Met | missense_variant | 47/49 | 5 | NM_001244008.2 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000322 AC: 80AN: 248418Hom.: 0 AF XY: 0.000245 AC XY: 33AN XY: 134964
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GnomAD4 exome AF: 0.000105 AC: 154AN: 1460118Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77AN XY: 726322
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GnomAD4 genome AF: 0.000191 AC: 29AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 26, 2018 | The KIF1A c.4852G>A; p.Val1618Met variant (rs200511467, ClinVar variant ID 464259), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a Latino population frequency of 0.2% (identified on 68 out of 34,318 chromosomes). The valine at position 1618 is moderately conserved, considering 13 species, and computational analyses of the effects of the p.Val1618Met variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Val1618Met variant cannot be determined with certainty. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Previously reported as V1719M due to alternative nomenclature, in individuals with an ataxic phenotype; however additional clinical details and segregation data were not provided (Vecchia et al., 2022); This variant is associated with the following publications: (PMID: 26125038, 21820098, 21376300, 34487232) - |
Hereditary spastic paraplegia 30 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
History of neurodevelopmental disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2019 | The p.V1618M variant (also known as c.4852G>A), located in coding exon 44 of the KIF1A gene, results from a G to A substitution at nucleotide position 4852. The valine at codon 1618 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
KIF1A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 16, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.;.;.;L;.;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
P;.;.;.;.;.;.;P;.;.;.;.;.;.
Vest4
0.54
MVP
0.39
MPC
0.93
ClinPred
T
GERP RS
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at