rs138935423

chr17-5022186-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006612.6(KIF1C):c.2105C>T(p.Thr702Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 1,614,108 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (60 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.603

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073581636).
• BP6: Variant 17-5022186-C-T is Benign according to our data. Variant chr17-5022186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 390510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00492 (750/152368) while in subpopulation NFE AF= 0.00923 (628/68036). AF 95% confidence interval is 0.00863. There are 2 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1C	NM_006612.6	c.2105C>T	p.Thr702Ile	missense_variant	22/23	ENST00000320785.10
KIF1C	XM_005256424.3	c.2105C>T	p.Thr702Ile	missense_variant	23/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1C	ENST00000320785.10	c.2105C>T	p.Thr702Ile	missense_variant	22/23	1	NM_006612.6	P1
KIF1C	ENST00000573815.1	n.647C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152250 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00923

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00473 AC: 1184 AN: 250276 Hom.: 4 AF XY: 0.00465 AC XY: 630 AN XY: 135606

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.00862

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00779 AC: 11384 AN: 1461740 Hom.: 60 Cov.: 32 AF XY: 0.00765 AC XY: 5565 AN XY: 727174

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.00467

Gnomad4 NFE exome AF: 0.00944

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.00492 AC: 750 AN: 152368 Hom.: 2 Cov.: 32 AF XY: 0.00397 AC XY: 296 AN XY: 74518

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00923

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00810 Hom.: 4

Bravo AF: 0.00450

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00469 AC: 569

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KIF1C: BS2 -

Spastic ataxia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.62	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.13	T
Polyphen		0.84	P
Vest4		0.37
MVP		0.78
MPC		1.0
ClinPred		0.0092	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.47

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: rs138935423; hg19: chr17-4925481;