2-240745878-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001244008.2(KIF1A):c.3234C>A(p.Ser1078Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,611,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S1078S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0110

Publications

0 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09592956).

BP6

Variant 2-240745878-G-T is Benign according to our data. Variant chr2-240745878-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532855.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000184 (28/152320) while in subpopulation AMR AF = 0.00124 (19/15308). AF 95% confidence interval is 0.000812. There are 0 homozygotes in GnomAd4. There are 10 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
KIF1A	NM_001244008.2 link	c.3234C>A	p.Ser1078Arg	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.3234C>A	p.Ser1078Arg	missense_variant	Exon 31 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.0000588

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.0000657

AC:

AN:

243348

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000352

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:

0.000675

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1458988

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

725510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.000450

AC:

AN:

44466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

85818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1110758

Other (OTH)

AF:

0.000166

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000184

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41576

American (AMR)

AF:

0.00124

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

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:

0.000135

Hom.:

Bravo

AF:

0.000306

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 02, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S977R variant (also known as c.2931C>A), located in coding exon 28 of the KIF1A gene, results from a C to A substitution at nucleotide position 2931. The serine at codon 977 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Intellectual disability, autosomal dominant 9

Uncertain:1

Jan 21, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jun 17, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9

Benign:1

Feb 03, 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

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

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

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.0

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.054

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

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.;.;M;.;.;.;.;.;.

PhyloP100

0.011

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.0

ClinPred

0.28

GERP RS

4.3

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.25

gMVP

0.84

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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