chr2-240745853-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001244008.2(KIF1A):c.3259C>T(p.Pro1087Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,612,358 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1087P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 30 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 3.39

Publications

7 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

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006913662).

BP6

Variant 2-240745853-G-A is Benign according to our data. Variant chr2-240745853-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196129.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0037 (563/152278) while in subpopulation NFE AF = 0.00591 (402/68006). AF 95% confidence interval is 0.00543. There are 0 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 30 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.3259C>T	p.Pro1087Ser	missense_variant	Exon 31 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.3259C>T	p.Pro1087Ser	missense_variant	Exon 31 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

562

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00590

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00368

AC:

901

AN:

244548

AF XY:

0.00387

show subpopulations

Gnomad AFR exome

AF:

0.00108

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.00244

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00174

Gnomad NFE exome

AF:

0.00562

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00460

AC:

6714

AN:

1460080

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

3412

AN XY:

726218

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33458

American (AMR)

AF:

0.00296

AC:

132

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

26050

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39672

South Asian (SAS)

AF:

0.00273

AC:

235

AN:

85958

European-Finnish (FIN)

AF:

0.00249

AC:

132

AN:

52918

Middle Eastern (MID)

AF:

0.00833

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00524

AC:

5829

AN:

1111394

Other (OTH)

AF:

0.00419

AC:

253

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

386

772

1159

1545

1931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00370

AC:

563

AN:

152278

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41556

American (AMR)

AF:

0.00457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00270

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

68006

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00466

Hom.:

Bravo

AF:

0.00335

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000513

AC:

ESP6500EA

AF:

0.00386

AC:

ExAC

AF:

0.00371

AC:

448

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00577

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:7

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIF1A: BP4, BS2

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21376300)

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

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:3

Sep 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 24, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 07, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia 30

Uncertain:1Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Benign:1

Feb 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

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 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

History of neurodevelopmental disorder

Benign:1

Mar 18, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico models in agreement (benign);Sub-population frequency in support of benign classification (not ava blue, manual h-w);Subpopulation frequency in support of benign classification

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.23

T;.;.;.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.0

.;D;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.0069

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.0

L;.;.;.;.;.;.;L;.;.;.;.;.;.

PhyloP100

3.4

PrimateAI

Benign

0.41

PROVEAN

Benign

0.0

.;N;D;.;.;.;.;.;.;.;.;.;D;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T;.;.;.;.;.;.;.;.;.;T;T

Sift4G

Pathogenic

0.0

.;T;T;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.0

ClinPred

0.0096

GERP RS

4.2

PromoterAI

-0.0046

Neutral

(source)

Varity_R

0.11

gMVP

0.65

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over