Variant 17-5000299-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006612.6(KIF1C):c.53G>A(p.Arg18His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,593,308 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.79

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1C	NM_006612.6 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	3/23	ENST00000320785.10	NP_006603.2	O43896
KIF1C	XM_005256424.3 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	4/24		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.53G>A	p.Arg18His	missense_variant	3/23	1	NM_006612.6	ENSP00000320821.5		O43896
KIF1C	ENST00000574165.1 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	4/7	5		ENSP00000458697.1		I3L1B1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1441122

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

715276

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000483

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000906

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The c.53G>A (p.R18H) alteration is located in exon 3 (coding exon 1) of the KIF1C gene. This alteration results from a G to A substitution at nucleotide position 53, causing the arginine (R) at amino acid position 18 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spastic ataxia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 31, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with KIF1C-related conditions. 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 sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 18 of the KIF1C protein (p.Arg18His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.98

D;.

Vest4

0.62

MutPred

0.67

Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);

MVP

0.87

MPC

1.1

ClinPred

0.94

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.83

gMVP

0.83

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