17-5023910-G-A

Position:

chr17-5023910-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.19

Variant links:

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]

KIF1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1C	ENST00000320785.10 linkuse as main transcript	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.:

Cov.:

show subpopulations

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.:

AF XY:

0.00189

AC XY:

208

AN XY:

110094

show subpopulations

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.:

Cov.:

AF XY:

0.00267

AC XY:

1853

AN XY:

694290

show subpopulations

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.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74376

show subpopulations

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.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00206

AC:

250

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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

KIF1C-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Benign

0.16

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.88

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.22

REVEL

Benign

0.17

Sift

Benign

0.058

Sift4G

Benign

0.54

Polyphen

0.98

Vest4

0.098

MVP

0.74

MPC

0.53

ClinPred

0.028

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over