17-5020056-C-T

Position:

chr17-5020056-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006612.6(KIF1C):c.1727C>T(p.Thr576Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,599,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.601

Variant links:

Genes affected

KIF1C (HGNC:6317): (kinesin family member 1C) The protein encoded by this gene is a member of the kinesin-like protein family. The family members are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. Mutations in this gene are a cause of spastic ataxia 2, autosomal recessive. [provided by RefSeq, May 2014]

KIF1C links:

KIF1C-AS1 (HGNC:40324): (KIF1C antisense RNA 1)

KIF1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09794405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KIF1C	NM_006612.6 linkuse as main transcript	c.1727C>T	p.Thr576Met	missense_variant	19/23	ENST00000320785.10	NP_006603.2
KIF1C-AS1	NR_120665.2 linkuse as main transcript	n.38G>A		non_coding_transcript_exon_variant	1/2
KIF1C	XM_005256424.3 linkuse as main transcript	c.1727C>T	p.Thr576Met	missense_variant	20/24		XP_005256481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KIF1C	ENST00000320785.10 linkuse as main transcript	c.1727C>T	p.Thr576Met	missense_variant	19/23	1	NM_006612.6	ENSP00000320821	P1
KIF1C-AS1	ENST00000438266.1 linkuse as main transcript	n.38G>A		non_coding_transcript_exon_variant	1/2	2
KIF1C	ENST00000573815.1 linkuse as main transcript	n.269C>T		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

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:

0.0000357

AC:

AN:

224386

Hom.:

AF XY:

0.0000249

AC XY:

AN XY:

120686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000126

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000734

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000200

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000297

AC:

AN:

1446878

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

718222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000188

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000479

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000253

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.000105

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000917

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:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic ataxia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 576 of the KIF1C protein (p.Thr576Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KIF1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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

Benign

0.080

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.81

M_CAP

Benign

0.018

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

0.99

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.24

Sift

Uncertain

0.025

Sift4G

Benign

0.061

Polyphen

0.018

Vest4

0.091

MVP

0.63

MPC

0.38

ClinPred

0.15

GERP RS

-0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.083

gMVP

0.67

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

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