17-5022380-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006612.6(KIF1C):c.2299G>A(p.Gly767Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,581,322 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. G767E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 8 hom. )

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.04

Publications

2 publications found

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012360156).

BP6

Variant 17-5022380-G-A is Benign according to our data. Variant chr17-5022380-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424674.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00154 (235/152392) while in subpopulation NFE AF = 0.00265 (180/68042). AF 95% confidence interval is 0.00233. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1C	NM_006612.6 link	c.2299G>A	p.Gly767Arg	missense_variant	Exon 22 of 23	ENST00000320785.10	NP_006603.2	O43896
KIF1C	XM_005256424.3 link	c.2299G>A	p.Gly767Arg	missense_variant	Exon 23 of 24		XP_005256481.1	O43896

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KIF1C	ENST00000320785.10 link	c.2299G>A	p.Gly767Arg	missense_variant	Exon 22 of 23	1	NM_006612.6	ENSP00000320821.5	O43896
KIF1C-AS1	ENST00000438266.2 link	n.172-1425C>T		intron_variant	Intron 1 of 3	2
KIF1C	ENST00000573815.1 link	n.*115G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

235

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00143

AC:

278

AN:

194866

AF XY:

0.00160

show subpopulations

Gnomad AFR exome

AF:

0.000519

Gnomad AMR exome

AF:

0.000354

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000697

Gnomad FIN exome

AF:

0.000221

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.000781

GnomAD4 exome

AF:

0.00271

AC:

3879

AN:

1428930

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1882

AN XY:

708146

show subpopulations

African (AFR)

AF:

0.000427

AC:

AN:

32772

American (AMR)

AF:

0.000280

AC:

AN:

39356

Ashkenazi Jewish (ASJ)

AF:

0.000236

AC:

AN:

25444

East Asian (EAS)

AF:

0.0000527

AC:

AN:

37940

South Asian (SAS)

AF:

0.00170

AC:

141

AN:

82830

European-Finnish (FIN)

AF:

0.000333

AC:

AN:

51072

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00330

AC:

3609

AN:

1094656

Other (OTH)

AF:

0.00132

AC:

AN:

59130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

248

496

744

992

1240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00154

AC:

235

AN:

152392

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41600

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00228

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

68042

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.00154

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00245

AC:

ExAC

AF:

0.000979

AC:

118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1Benign:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 17, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIF1C: BS2 -

Jun 18, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

KIF1C-related disorder

Benign:1

Feb 04, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Spastic ataxia 2

Benign:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

0.033

Eigen_PC

Benign

0.060

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.035

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.0

PhyloP100

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

REVEL

Benign

0.17

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.032

Polyphen

0.97

Vest4

0.45

MutPred

0.23

Loss of methylation at R768 (P = 0.0668);

MVP

0.69

MPC

0.43

ClinPred

0.015

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.089

gMVP

0.65

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over