2-240775931-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001244008.2(KIF1A):​c.883-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,599,922 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000094 ( 1 hom. )

Consequence

KIF1A
NM_001244008.2 splice_region, intron

Scores

2
Splicing: ADA: 0.002302
2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.323
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 Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BP6
Variant 2-240775931-G-T is Benign according to our data. Variant chr2-240775931-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 464264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240775931-G-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000473 (72/152336) while in subpopulation AFR AF= 0.0014 (58/41560). AF 95% confidence interval is 0.00111. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.883-5C>A splice_region_variant, intron_variant Intron 10 of 48 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.883-5C>A splice_region_variant, intron_variant Intron 10 of 48 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
AF:
0.000473
AC:
72
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00140
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
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:
0.0000882
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000137
AC:
34
AN:
248800
Hom.:
0
AF XY:
0.0000962
AC XY:
13
AN XY:
135086
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.0000871
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.0000887
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000939
AC:
136
AN:
1447586
Hom.:
1
Cov.:
27
AF XY:
0.0000874
AC XY:
63
AN XY:
721068
show subpopulations
Gnomad4 AFR exome
AF:
0.00118
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000764
Gnomad4 OTH exome
AF:
0.000117
GnomAD4 genome
AF:
0.000473
AC:
72
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.000470
AC XY:
35
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.00140
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000223
Hom.:
0
Bravo
AF:
0.000586
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 25, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

KIF1A: BP4 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
May 24, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KIF1A-related disorder Benign:1
Aug 15, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
-0.76
CADD
Benign
5.0
DANN
Benign
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0023
dbscSNV1_RF
Benign
0.072
SpliceAI score (max)
0.060
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: rs201408083; hg19: chr2-241715348; API