rs146872023

chr17-5003999-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006612.6(KIF1C):c.866A>C(p.Gln289Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0014 in 1,613,864 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: KIF1C NM_006612.6 missense, splice_region
• Scores: Splicing: ADA: 0.8663
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.03

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05489394).
• BP6: Variant 17-5003999-A-C is Benign according to our data. Variant chr17-5003999-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425119.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• 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.866A>C	p.Gln289Pro	missense_variant, splice_region_variant	11/23	ENST00000320785.10
KIF1C	XM_005256424.3	c.866A>C	p.Gln289Pro	missense_variant, splice_region_variant	12/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1C	ENST00000320785.10	c.866A>C	p.Gln289Pro	missense_variant, splice_region_variant	11/23	1	NM_006612.6	P1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00111 AC: 279 AN: 251488 Hom.: 2 AF XY: 0.00125 AC XY: 170 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00144 AC: 2102 AN: 1461692 Hom.: 4 Cov.: 31 AF XY: 0.00146 AC XY: 1060 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74392

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.000994

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00124 AC: 151

EpiCase AF: 0.00229

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	KIF1C: BS2 -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Spastic ataxia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.055	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.027	D
Polyphen		0.97	D
Vest4		0.31
MVP		0.91
MPC		1.0
ClinPred		0.068	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.63
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: rs146872023; hg19: chr17-4907294;