chr2-240741338-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001244008.2(KIF1A):​c.3680C>G​(p.Pro1227Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1227L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.72

Publications

2 publications found
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]
KIF1A Gene-Disease associations (from GenCC):
  • intellectual disability, autosomal dominant 9
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • syndromic intellectual disability
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • neuropathy, hereditary sensory, type 2C
    Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • hereditary spastic paraplegia 30
    Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • autosomal dominant non-syndromic intellectual disability
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • PEHO syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary sensory and autonomic neuropathy type 2
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2456555).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.3680C>G p.Pro1227Arg 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.3680C>G p.Pro1227Arg missense_variant Exon 35 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
218374
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1441294
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
715808
African (AFR)
AF:
0.00
AC:
0
AN:
33238
American (AMR)
AF:
0.00
AC:
0
AN:
42946
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25888
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39040
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83662
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
45230
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1105736
Other (OTH)
AF:
0.00
AC:
0
AN:
59812
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.042
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
-0.0027
Eigen_PC
Benign
0.030
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Benign
0.079
D
MetaRNN
Benign
0.25
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.46
N;.;.;.;.;.;.;N;.;.;.;.;.;.
PhyloP100
5.7
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-2.7
.;D;N;.;.;.;.;.;.;.;.;.;.;N
REVEL
Benign
0.17
Sift
Benign
0.050
.;D;D;.;.;.;.;.;.;.;.;.;.;T
Sift4G
Benign
0.33
.;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen
0.60
P;.;.;.;.;.;.;P;.;.;.;.;.;P
Vest4
0.33, 0.29
MutPred
0.30
Gain of solvent accessibility (P = 0.0216);.;Gain of solvent accessibility (P = 0.0216);.;.;Gain of solvent accessibility (P = 0.0216);.;Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);.;.;.;.;.;
MVP
0.58
MPC
0.70
ClinPred
0.88
D
GERP RS
4.3
Varity_R
0.073
gMVP
0.23
Mutation Taster
=95/5
polymorphism

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

Other links and lift over

dbSNP: rs374244985; hg19: chr2-241680755; API