rs141225452

chr17-5023910-G-Achr17-5023910-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_006612.6(KIF1C):c.3071G>A(p.Arg1024Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,558,586 control chromosomes in the GnomAD database, including 7 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1024P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: KIF1C NM_006612.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.19

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007027447).
• BP6: Variant 17-5023910-G-A is Benign according to our data. Variant chr17-5023910-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 390925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-5023910-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00275 (3866/1406404) while in subpopulation NFE AF= 0.00333 (3607/1083842). AF 95% confidence interval is 0.00324. There are 7 homozygotes in gnomad4_exome. There are 1853 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1C	NM_006612.6	c.3071G>A	p.Arg1024Gln	missense_variant	23/23	ENST00000320785.10
KIF1C	XM_005256424.3	c.3071G>A	p.Arg1024Gln	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1C	ENST00000320785.10	c.3071G>A	p.Arg1024Gln	missense_variant	23/23	1	NM_006612.6	P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00186 AC: 380 AN: 204758 Hom.: 1 AF XY: 0.00189 AC XY: 208 AN XY: 110094

Gnomad AFR exome AF: 0.000519

Gnomad AMR exome AF: 0.000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000355

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00275 AC: 3866 AN: 1406404 Hom.: 7 Cov.: 35 AF XY: 0.00267 AC XY: 1853 AN XY: 694290

Gnomad4 AFR exome AF: 0.000221

Gnomad4 AMR exome AF: 0.000192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00186

Gnomad4 NFE exome AF: 0.00333

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74376

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00175

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KIF1C: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

KIF1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2023

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). -

Spastic ataxia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.88	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.17
Sift	Benign	0.058	T
Sift4G	Benign	0.54	T
Polyphen		0.98	D
Vest4		0.098
MVP		0.74
MPC		0.53
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.035
gMVP		0.25

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: rs141225452; hg19: chr17-4927205;