chr2-240722517-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001244008.2(KIF1A):c.4604C>T(p.Ala1535Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,548,294 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0045 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 53 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 2.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in the KIF1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 112 curated pathogenic missense variants (we use a threshold of 10). The gene has 150 curated benign missense variants. Gene score misZ: 5.1579 (above the threshold of 3.09). Trascript score misZ: 5.0191 (above the threshold of 3.09). GenCC associations: The gene is linked to neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037439167).

BP6

Variant 2-240722517-G-A is Benign according to our data. Variant chr2-240722517-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211288.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=3}. Variant chr2-240722517-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (679/152284) while in subpopulation NFE AF= 0.00849 (577/68000). AF 95% confidence interval is 0.00791. There are 2 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.4604C>T	p.Ala1535Val	missense_variant	Exon 43 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.4604C>T	p.Ala1535Val	missense_variant	Exon 43 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

679

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00848

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00379

AC:

572

AN:

151034

Hom.:

AF XY:

0.00369

AC XY:

298

AN XY:

80752

show subpopulations

Gnomad AFR exome

AF:

0.00146

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.000477

Gnomad EAS exome

AF:

0.000184

Gnomad SAS exome

AF:

0.000528

Gnomad FIN exome

AF:

0.000866

Gnomad NFE exome

AF:

0.00856

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00748

AC:

10446

AN:

1396010

Hom.:

Cov.:

AF XY:

0.00741

AC XY:

5104

AN XY:

688566

show subpopulations

Gnomad4 AFR exome

AF:

0.00127

Gnomad4 AMR exome

AF:

0.00118

Gnomad4 ASJ exome

AF:

0.000398

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.000379

Gnomad4 FIN exome

AF:

0.00162

Gnomad4 NFE exome

AF:

0.00917

Gnomad4 OTH exome

AF:

0.00612

GnomAD4 genome

AF:

0.00446

AC:

679

AN:

152284

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00849

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00615

Hom.:

Bravo

AF:

0.00452

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00196

AC:

ESP6500EA

AF:

0.00516

AC:

ExAC

AF:

0.00150

AC:

140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Mar 19, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF1A: BP4, BS2 -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Oct 30, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Intellectual disability, autosomal dominant 9

Uncertain:1

Oct 12, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 30

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary spastic paraplegia

Benign:1

Jul 03, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KIF1A-related disorder

Benign:1

Nov 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

History of neurodevelopmental disorder

Benign:1

Dec 18, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico models in agreement (benign);Other strong data;Other strong data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.042

MetaRNN

Benign

0.0037

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

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

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.064

Sift

Benign

0.054

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

Sift4G

Benign

0.11

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

Polyphen

0.0

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

Vest4

0.16

MVP

0.47

MPC

0.43

ClinPred

0.020

GERP RS

3.6

Varity_R

0.063

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over