rs752648536

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001365951.3(KIF1B):c.1855C>T(p.Arg619Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R619H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.92

Variant links:

Genes affected

KIF1B (HGNC:16636): (kinesin family member 1B) Predicted to enable microtubule binding activity and plus-end-directed microtubule motor activity. Predicted to be involved in chemical synaptic transmission; dense core granule cytoskeletal transport; and vesicle-mediated transport. Predicted to act upstream of or within mitochondrion transport along microtubule. Predicted to be located in cytoplasmic vesicle membrane and neuron projection. Predicted to be part of kinesin complex. Predicted to be active in several cellular components, including axon; dendrite; and microtubule. Implicated in Charcot-Marie-Tooth disease type 2A1; carcinoma (multiple); multiple sclerosis; neuroblastoma; and pheochromocytoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

KIF1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant where missense usually causes diseases, KIF1B

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

BS2

High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3 linkuse as main transcript	c.1855C>T	p.Arg619Cys	missense_variant	20/49	ENST00000676179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.1855C>T	p.Arg619Cys	missense_variant	20/49		NM_001365951.3	P1	O60333-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251178

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461200

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The p.R573C variant (also known as c.1717C>T), located in coding exon 17 of the KIF1B gene, results from a C to T substitution at nucleotide position 1717. The arginine at codon 573 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 573 of the KIF1B protein (p.Arg573Cys). This variant is present in population databases (rs752648536, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KIF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 216685). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.4

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

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

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.61

MutPred

0.64

.;.;Loss of MoRF binding (P = 0.0142);.;Loss of MoRF binding (P = 0.0142);.;.;

MVP

0.87

MPC

2.3

ClinPred

0.89

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.64

gMVP

0.85

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