rs148934699

chr17-5022180-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006612.6(KIF1C):c.2099C>T(p.Pro700Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,614,030 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P700P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (30 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0282045).
• BP6: Variant 17-5022180-C-T is Benign according to our data. Variant chr17-5022180-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209166.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=4}. Variant chr17-5022180-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0032 (488/152352) while in subpopulation NFE AF= 0.00541 (368/68030). AF 95% confidence interval is 0.00495. There are 0 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1C	NM_006612.6	c.2099C>T	p.Pro700Leu	missense_variant	22/23	ENST00000320785.10
KIF1C	XM_005256424.3	c.2099C>T	p.Pro700Leu	missense_variant	23/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1C	ENST00000320785.10	c.2099C>T	p.Pro700Leu	missense_variant	22/23	1	NM_006612.6	P1
KIF1C	ENST00000573815.1	n.641C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00292 AC: 729 AN: 250052 Hom.: 2 AF XY: 0.00289 AC XY: 391 AN XY: 135528

Gnomad AFR exome AF: 0.000819

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000926

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00496 AC: 7249 AN: 1461678 Hom.: 30 Cov.: 32 AF XY: 0.00477 AC XY: 3465 AN XY: 727130

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00604

Gnomad4 OTH exome AF: 0.00470

GnomAD4 genome AF: 0.00320 AC: 488 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74504

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00475 Hom.: 1

Bravo AF: 0.00320

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00315 AC: 382

EpiCase AF: 0.00469

EpiControl AF: 0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	This variant is associated with the following publications: (PMID: 26633545) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	KIF1C: BS2 -

Spastic ataxia 2 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic ataxia 2 (MIM#611302). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of spastic ataxia 2 (MIM#611302). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The most recent entries in Clinvar have classified this variant as either likely benign or a variant of uncertain significance (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 21, 2022

- -

KIF1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.86
MPC		1.0
ClinPred		0.028	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.81

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

Other links and lift over

dbSNP: rs148934699; hg19: chr17-4925475;