rs202232792

Positions:

chr17-5023573-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006612.6(KIF1C):c.2734C>T(p.Arg912Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,520 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.0840

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055503547).

BP6

Variant 17-5023573-C-T is Benign according to our data. Variant chr17-5023573-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209167.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00157 (2298/1461312) while in subpopulation EAS AF= 0.00715 (284/39700). AF 95% confidence interval is 0.00647. There are 7 homozygotes in gnomad4_exome. There are 1120 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1C	NM_006612.6 linkuse as main transcript	c.2734C>T	p.Arg912Trp	missense_variant	23/23	ENST00000320785.10	NP_006603.2	O43896
KIF1C	XM_005256424.3 linkuse as main transcript	c.2734C>T	p.Arg912Trp	missense_variant	24/24		XP_005256481.1	O43896

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1C	ENST00000320785.10 linkuse as main transcript	c.2734C>T	p.Arg912Trp	missense_variant	23/23	1	NM_006612.6	ENSP00000320821.5		O43896

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00426

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00148

AC:

366

AN:

246712

Hom.:

AF XY:

0.00139

AC XY:

186

AN XY:

134260

show subpopulations

Gnomad AFR exome

AF:

0.0000640

Gnomad AMR exome

AF:

0.000696

Gnomad ASJ exome

AF:

0.00713

Gnomad EAS exome

AF:

0.00269

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00183

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00157

AC:

2298

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1120

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00655

Gnomad4 EAS exome

AF:

0.00715

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000509

Gnomad4 NFE exome

AF:

0.00150

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152208

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00427

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00133

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00153

AC:

185

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 01, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -

Spastic ataxia 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KIF1C: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	This variant is associated with the following publications: (PMID: 26633545, 31101064, 28832565) -

KIF1C-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.087

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

REVEL

Benign

0.23

Sift

Benign

0.039

Sift4G

Uncertain

0.016

Polyphen

0.99

Vest4

0.17

MVP

0.76

MPC

0.38

ClinPred

0.041

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.072

gMVP

0.24

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