17-5004946-G-A

Position:

chr17-5004946-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006612.6(KIF1C):c.1111G>A(p.Ala371Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,614,248 control chromosomes in the GnomAD database, including 20 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 19 hom. )

Consequence

KIF1C
NM_006612.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.13

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01151219).

BP6

Variant 17-5004946-G-A is Benign according to our data. Variant chr17-5004946-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424675.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00355 (541/152368) while in subpopulation NFE AF= 0.00525 (357/68040). AF 95% confidence interval is 0.0048. There are 1 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1C	NM_006612.6 linkuse as main transcript	c.1111G>A	p.Ala371Thr	missense_variant	13/23	ENST00000320785.10
KIF1C	XM_005256424.3 linkuse as main transcript	c.1111G>A	p.Ala371Thr	missense_variant	14/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1C	ENST00000320785.10 linkuse as main transcript	c.1111G>A	p.Ala371Thr	missense_variant	13/23	1	NM_006612.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00355

AC:

541

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00525

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00337

AC:

847

AN:

251406

Hom.:

AF XY:

0.00327

AC XY:

444

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00661

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00434

AC:

6342

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

3109

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00253

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.00687

Gnomad4 NFE exome

AF:

0.00497

Gnomad4 OTH exome

AF:

0.00323

GnomAD4 genome

AF:

0.00355

AC:

541

AN:

152368

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.00525

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00431

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00351

AC:

426

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 29, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic ataxia 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

KIF1C: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.017

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.70

REVEL

Benign

0.15

Sift

Benign

0.81

Sift4G

Benign

0.65

Polyphen

0.92

Vest4

0.17

MVP

0.73

MPC

0.44

ClinPred

0.030

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.10

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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