2-240766948-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001244008.2(KIF1A):c.1651G>A(p.Val551Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,611,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.000053 ( 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:2B:1

Conservation

PhyloP100: 0.499

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031081825).

BP6

Variant 2-240766948-C-T is Benign according to our data. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561. Variant chr2-240766948-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 444561.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.1651G>A	p.Val551Ile	missense_variant	Exon 19 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.1651G>A	p.Val551Ile	missense_variant	Exon 19 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000691

AC:

AN:

246170

AF XY:

0.0000672

show subpopulations

Gnomad AFR exome

AF:

0.0000664

Gnomad AMR exome

AF:

0.000175

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:

0.000168

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459722

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726004

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.000126

AC:

AN:

39686

South Asian (SAS)

AF:

0.000384

AC:

AN:

85920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111426

Other (OTH)

AF:

0.000149

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000526

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41416

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 07, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; This amino acid substitution does not occur within the predicted motor domain of the protein, where most pathogenic missense variants in KIF1A have been identified (Lee et al., 2015).; In silico analysis supports that this missense variant does not alter protein structure/function -

Apr 01, 2017

CeGaT Center for Human Genetics Tuebingen

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

Nov 26, 2024

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

Benign

0.054

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.22

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.80

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.031

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

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.57

N;.;.;.;.;.;.;N;.;.;.;.;.

PhyloP100

0.50

PrimateAI

Benign

0.42

PROVEAN

Benign

0.0

.;N;N;.;.;.;.;.;.;.;.;.;N

REVEL

Benign

0.15

Sift

Benign

1.0

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

Sift4G

Benign

0.71

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

Polyphen

0.0010

B;.;.;.;.;.;.;B;.;.;.;.;B

Vest4

0.089, 0.051

MVP

0.23

MPC

0.99

ClinPred

0.015

GERP RS

-0.095

Varity_R

0.042

gMVP

0.77

Mutation Taster

=92/8

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