Genetic Variant NM_006612.6:c.41C>T (chr17-5000287-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_006612.6(KIF1C):c.41C>T(p.Pro14Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.01

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 Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 17-5000287-C-T is Pathogenic according to our data. Variant chr17-5000287-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2444164.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1C	NM_006612.6 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 3 of 23	ENST00000320785.10	NP_006603.2	O43896
KIF1C	XM_005256424.3 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 4 of 24		XP_005256481.1	O43896

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1C	ENST00000320785.10 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 3 of 23	1	NM_006612.6	ENSP00000320821.5		O43896
KIF1C	ENST00000574165.1 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 4 of 7	5		ENSP00000458697.1		I3L1B1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1436110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712332

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic ataxia 2

Pathogenic:1

Feb 19, 2024

3billion, Medical Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 14594949, 19150977). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.57 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014067 /PMID: 9535554 /3billion dataset). A different missense change at the same codon (p.Arg58Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000532778 /PMID: 24793961). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-9.5

D;.

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0010

B;.

Vest4

0.91

MutPred

0.83

Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);

MVP

0.93

MPC

1.1

ClinPred

0.96

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.77

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over