2-240741274-G-C

Variant summary

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

The NM_001244008.2(KIF1A):​c.3744C>G​(p.Asn1248Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

KIF1A
NM_001244008.2 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.24
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]

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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=0.25050485).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.3744C>G p.Asn1248Lys missense_variant Exon 35 of 49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.3744C>G p.Asn1248Lys missense_variant Exon 35 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Uncertain:1
Jun 25, 2021
New York Genome Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
0.21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.61
D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.15
N
LIST_S2
Uncertain
0.96
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.25
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Uncertain
2.4
M;.;.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-4.2
.;D;D;.;.;.;.;.;.;.;.;.;.;D
REVEL
Benign
0.23
Sift
Uncertain
0.0070
.;D;D;.;.;.;.;.;.;.;.;.;.;D
Sift4G
Uncertain
0.045
.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
0.99
D;.;.;.;.;.;.;D;.;.;.;.;.;B
Vest4
0.51, 0.56
MutPred
0.45
Gain of ubiquitination at N1147 (P = 0.0203);.;Gain of ubiquitination at N1147 (P = 0.0203);.;.;Gain of ubiquitination at N1147 (P = 0.0203);.;Gain of ubiquitination at N1147 (P = 0.0203);Gain of ubiquitination at N1147 (P = 0.0203);.;.;.;.;.;
MVP
0.64
MPC
0.79
ClinPred
0.87
D
GERP RS
-8.9
Varity_R
0.55
gMVP
0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-241680691; API