chr2-240770983-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001244008.2(KIF1A):ā€‹c.1329T>Gā€‹(p.Ile443Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.65
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the KIF1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 112 curated pathogenic missense variants (we use a threshold of 10). The gene has 150 curated benign missense variants. Gene score misZ: 5.1579 (above the threshold of 3.09). Trascript score misZ: 5.0191 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.1913226).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF1ANM_001244008.2 linkc.1329T>G p.Ile443Met missense_variant 15/49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.1329T>G p.Ile443Met missense_variant 15/495 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248162
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134730
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459178
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725866
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000826
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.035
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
0.71
DANN
Benign
0.94
DEOGEN2
Benign
0.23
T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.19
N
LIST_S2
Uncertain
0.90
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.19
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.4
L;.;.;.;.;.;.;L;.;.;.;.;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.3
.;N;N;.;.;.;.;.;.;.;.;.;N;.
REVEL
Uncertain
0.35
Sift
Benign
0.21
.;T;T;.;.;.;.;.;.;.;.;.;T;.
Sift4G
Benign
0.13
.;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4
0.79, 0.74
MutPred
0.38
Loss of catalytic residue at I434 (P = 0.0173);.;Loss of catalytic residue at I434 (P = 0.0173);.;.;Loss of catalytic residue at I434 (P = 0.0173);Loss of catalytic residue at I434 (P = 0.0173);Loss of catalytic residue at I434 (P = 0.0173);Loss of catalytic residue at I434 (P = 0.0173);.;Loss of catalytic residue at I434 (P = 0.0173);.;.;.;
MVP
0.61
MPC
2.4
ClinPred
0.13
T
GERP RS
-2.4
Varity_R
0.43
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs761314693; hg19: chr2-241710400; API