chr17-5023910-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_006612.6(KIF1C):c.3071G>C(p.Arg1024Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,558,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. R1024Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19

Publications

5 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23872164).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000391 (55/1406406) while in subpopulation MID AF = 0.000365 (2/5474). AF 95% confidence interval is 0.0000639. There are 0 homozygotes in GnomAdExome4. There are 32 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006612.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	NM_006612.6	MANE Select	c.3071G>C	p.Arg1024Pro	missense	Exon 23 of 23	NP_006603.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1C	ENST00000320785.10	TSL:1 MANE Select	c.3071G>C	p.Arg1024Pro	missense	Exon 23 of 23	ENSP00000320821.5
	KIF1C-AS1	ENST00000438266.2	TSL:2	n.172-2955C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000440

AC:

AN:

204758

AF XY:

0.0000636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000863

Gnomad OTH exome

AF:

0.000207

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1406406

Hom.:

Cov.:

AF XY:

0.0000461

AC XY:

AN XY:

694292

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31614

American (AMR)

AF:

0.00

AC:

AN:

36482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22326

East Asian (EAS)

AF:

0.00

AC:

AN:

38946

South Asian (SAS)

AF:

0.00

AC:

AN:

78338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51536

Middle Eastern (MID)

AF:

0.000365

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.0000452

AC:

AN:

1083844

Other (OTH)

AF:

0.0000519

AC:

AN:

57846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000151

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic ataxia 2

Uncertain:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1024 of the KIF1C protein (p.Arg1024Pro). This variant is present in population databases (rs141225452, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with KIF1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 2039348). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.69

PhyloP100

2.2

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.25

REVEL

Benign

0.20

Sift

Uncertain

0.020

Sift4G

Benign

0.32

Polyphen

0.99

Vest4

0.27

MutPred

0.22

Gain of glycosylation at R1024 (P = 0.0045)

MVP

0.78

MPC

0.83

ClinPred

0.22

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.33

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over