11-66265058-C-T

Position:

chr11-66265058-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001318734.2(KLC2):c.1252C>T(p.Arg418Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,612,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

KLC2
NM_001318734.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.372

Variant links:

Genes affected

KLC2 (HGNC:20716): (kinesin light chain 2) The protein encoded by this gene is a light chain of kinesin, a molecular motor responsible for moving vesicles and organelles along microtubules. Defects in this gene are a cause of spastic paraplegia, optic atrophy, and neuropathy (SPOAN) syndrome. [provided by RefSeq, Mar 2016]

KLC2 links:

KLC2-AS1 (HGNC:):

KLC2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLC2	NM_001318734.2 linkuse as main transcript	c.1252C>T	p.Arg418Trp	missense_variant	10/16	ENST00000394067.7	NP_001305663.1	Q9H0B6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLC2	ENST00000394067.7 linkuse as main transcript	c.1252C>T	p.Arg418Trp	missense_variant	10/16	1	NM_001318734.2	ENSP00000377631.2		Q9H0B6-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

250850

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000524

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1460540

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000534

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1252C>T (p.R418W) alteration is located in exon 10 (coding exon 9) of the KLC2 gene. This alteration results from a C to T substitution at nucleotide position 1252, causing the arginine (R) at amino acid position 418 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with KLC2-related conditions. This variant is present in population databases (rs561576772, gnomAD 0.05%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 418 of the KLC2 protein (p.Arg418Trp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;T;.;T;.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.66

LIST_S2

Pathogenic

1.0

D;.;D;.;.;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.48

T;T;T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.8

M;M;.;M;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.2

D;D;D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;.;D

Vest4

0.68

MutPred

0.40

Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);.;Loss of disorder (P = 0.0149);.;.;

MVP

0.88

MPC

1.5

ClinPred

0.64

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.89

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