chr2-240742952-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_001244008.2(KIF1A):​c.3617G>A​(p.Arg1206Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,526 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 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

1
5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.83
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ: 5.1579 (greater than the threshold 3.09). Trascript score misZ: 5.0191 (greater than threshold 3.09). The gene has 112 curated pathogenic missense variants (we use a threshold of 10). The gene has 150 curated benign missense variants. GenCC has associacion of the gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
BP4
Computational evidence support a benign effect (MetaRNN=0.24185964).
BP6
Variant 2-240742952-C-T is Benign according to our data. Variant chr2-240742952-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 588171.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF1ANM_001244008.2 linkc.3617G>A p.Arg1206Gln missense_variant 34/49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.3617G>A p.Arg1206Gln missense_variant 34/495 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000815
AC:
2
AN:
245286
Hom.:
0
AF XY:
0.00000749
AC XY:
1
AN XY:
133470
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000333
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000901
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1459374
Hom.:
0
Cov.:
30
AF XY:
0.0000386
AC XY:
28
AN XY:
725838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000358
AC:
3
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 10, 2023Reported previously in two siblings with early onset familial ALS; however, no further clinical information was provided (Liao et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36284339) -
History of neurodevelopmental disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 19, 2016The p.R1105Q variant (also known as c.3314G>A), located in coding exon 31 of the KIF1A gene, results from a G to A substitution at nucleotide position 3314. The arginine at codon 1105 is replaced by glutamine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs369849214. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (3/12498) total alleles studied and 0.04% (3/8382) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. 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. -
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.13
T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
0.19
Eigen_PC
Benign
0.14
FATHMM_MKL
Benign
0.56
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.24
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.1
M;.;.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.0
.;N;N;.;.;.;.;.;.;.;.;.;.;N
REVEL
Benign
0.21
Sift
Benign
0.18
.;T;T;.;.;.;.;.;.;.;.;.;.;T
Sift4G
Benign
0.59
.;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;D;.;.;.;.;.;D
Vest4
0.37, 0.36
MVP
0.67
MPC
0.53
ClinPred
0.55
D
GERP RS
4.6
Varity_R
0.10
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369849214; hg19: chr2-241682369; API