rs115332491

Positions:

• chr17-5023826-G-A

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.2987G>A​(p.Ser996Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,518,520 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (73 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.833

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=0.0017690659).
• BP6: Variant 17-5023826-G-A is Benign according to our data. Variant chr17-5023826-G-A is described in ClinVar as [Benign]. Clinvar id is 468856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0144 (2196/152220) while in subpopulation EAS AF= 0.0522 (269/5158). AF 95% confidence interval is 0.047. There are 43 homozygotes in gnomad4. There are 1041 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1C	NM_006612.6	c.2987G>A	p.Ser996Asn	missense_variant	23/23	ENST00000320785.10	NP_006603.2
KIF1C	XM_005256424.3	c.2987G>A	p.Ser996Asn	missense_variant	24/24		XP_005256481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1C	ENST00000320785.10	c.2987G>A	p.Ser996Asn	missense_variant	23/23	1	NM_006612.6	ENSP00000320821.5

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 152102 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00915 AC: 1565 AN: 171012 Hom.: 35 AF XY: 0.00745 AC XY: 677 AN XY: 90894

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00619

Gnomad EAS exome AF: 0.0533

Gnomad SAS exome AF: 0.000342

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00268 AC: 3657 AN: 1366300 Hom.: 73 Cov.: 35 AF XY: 0.00247 AC XY: 1651 AN XY: 669546

Gnomad4 AFR exome AF: 0.0440

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0443

Gnomad4 SAS exome AF: 0.000920

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000628

Gnomad4 OTH exome AF: 0.00602

GnomAD4 genome AF: 0.0144 AC: 2196 AN: 152220 Hom.: 43 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74408

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0522

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00947 Hom.: 9

Bravo AF: 0.0167

ESP6500AA AF: 0.0434 AC: 189

ESP6500EA AF: 0.000352 AC: 3

ExAC AF: 0.00787 AC: 933

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2019	This variant is associated with the following publications: (PMID: 32501971) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KIF1C: BS1, BS2 -

KIF1C-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spastic ataxia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.11
Sift	Benign	0.40	T
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.044
MVP		0.42
MPC		0.31
ClinPred		0.00080	T
GERP RS		0.20
Varity_R		0.022
gMVP		0.090

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: rs115332491; hg19: chr17-4927121;