2-240719906-C-T

Position:

chr2-240719906-C-T

Variant summary

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

The NM_001244008.2(KIF1A):c.4889G>A(p.Arg1630Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,610,628 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1630W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 8 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 3.76

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 where missense usually causes diseases, KIF1A

BP4

Computational evidence support a benign effect (MetaRNN=0.006158352).

BP6

Variant 2-240719906-C-T is Benign according to our data. Variant chr2-240719906-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 335256.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=1}. Variant chr2-240719906-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00219 (334/152272) while in subpopulation EAS AF= 0.000964 (5/5186). AF 95% confidence interval is 0.000495. There are 5 homozygotes in gnomad4. There are 244 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.4889G>A	p.Arg1630Gln	missense_variant	46/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.4889G>A	p.Arg1630Gln	missense_variant	46/49	5	NM_001244008.2		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

334

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00257

AC:

628

AN:

243946

Hom.:

AF XY:

0.00262

AC XY:

349

AN XY:

133082

show subpopulations

Gnomad AFR exome

AF:

0.000264

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00101

Gnomad SAS exome

AF:

0.000362

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.00129

AC:

1880

AN:

1458356

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

943

AN XY:

725450

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00242

Gnomad4 SAS exome

AF:

0.000465

Gnomad4 FIN exome

AF:

0.0176

Gnomad4 NFE exome

AF:

0.000681

Gnomad4 OTH exome

AF:

0.000980

GnomAD4 genome

AF:

0.00219

AC:

334

AN:

152272

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

244

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0253

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000478

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.000719

AC:

ExAC

AF:

0.00225

AC:

271

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000892

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2016

A variant of uncertain significance has been identified in the KIF1A gene. The R1529Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1529Q variant was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project but the 1000 Genomes Project reports R1529Q was observed in 8/198 (4.0%) alleles from individuals of Finnish background, indicating it may be a rare (benign) variant in this population. The R1529Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, this amino acid substitution does not occur within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hereditary spastic paraplegia 30

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2021

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

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

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.91

MetaRNN

Benign

0.0062

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

Polyphen

0.94

P;.;.;.;.;.;.;P;.;.;.;.;.;.

Vest4

0.34

MVP

0.55

MPC

1.0

ClinPred

0.048

GERP RS

4.2

Varity_R

0.14

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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