2-240744058-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6BP7BS1

The NM_001244008.2(KIF1A):​c.3468C>T​(p.Ile1156Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000648 in 1,604,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I1156I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 splice_region, synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.599

Publications

1 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: Likely_benign. The variant received -6 ACMG points.

BP6
Variant 2-240744058-G-A is Benign according to our data. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285. Variant chr2-240744058-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211285.
BP7
Synonymous conserved (PhyloP=-0.599 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000315 (48/152328) while in subpopulation AFR AF = 0.00106 (44/41570). AF 95% confidence interval is 0.00081. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.3468C>T p.Ile1156Ile splice_region_variant, synonymous_variant Exon 33 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.3468C>T p.Ile1156Ile splice_region_variant, synonymous_variant Exon 33 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
AF:
0.000309
AC:
47
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000964
AC:
24
AN:
248846
AF XY:
0.0000741
show subpopulations
Gnomad AFR exome
AF:
0.000969
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000497
GnomAD4 exome
AF:
0.0000386
AC:
56
AN:
1452072
Hom.:
0
Cov.:
28
AF XY:
0.0000346
AC XY:
25
AN XY:
722882
show subpopulations
African (AFR)
AF:
0.000691
AC:
23
AN:
33296
American (AMR)
AF:
0.000134
AC:
6
AN:
44690
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26062
East Asian (EAS)
AF:
0.0000505
AC:
2
AN:
39638
South Asian (SAS)
AF:
0.0000465
AC:
4
AN:
86018
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53294
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.0000127
AC:
14
AN:
1103256
Other (OTH)
AF:
0.000117
AC:
7
AN:
60068
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000315
AC:
48
AN:
152328
Hom.:
0
Cov.:
33
AF XY:
0.000322
AC XY:
24
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.00106
AC:
44
AN:
41570
American (AMR)
AF:
0.000261
AC:
4
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000247
Hom.:
0
Bravo
AF:
0.000468

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Jan 21, 2019
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 15, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Nov 04, 2014
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.51
CADD
Benign
5.7
DANN
Benign
0.83
PhyloP100
-0.60
Mutation Taster
=95/5
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs201981364; hg19: chr2-241683475; API