Genetic Variant KLC2:p.Arg426Trp (chr11-66265177-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001318734.2(KLC2):c.1276C>T(p.Arg426Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000289 in 1,487,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

KLC2
NM_001318734.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.31

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:40934): (KLC2 antisense RNA 1)

KLC2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38813657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLC2	NM_001318734.2 link	c.1276C>T	p.Arg426Trp	missense_variant	Exon 11 of 16	ENST00000394067.7	NP_001305663.1	Q9H0B6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLC2	ENST00000394067.7 link	c.1276C>T	p.Arg426Trp	missense_variant	Exon 11 of 16	1	NM_001318734.2	ENSP00000377631.2		Q9H0B6-1

Frequencies

GnomAD3 genomes

AF:

0.0000671

AC:

AN:

149028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251342

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000254

AC:

AN:

1338550

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

665684

show subpopulations

Gnomad4 AFR exome

AF:

0.0000339

Gnomad4 AMR exome

AF:

0.000172

Gnomad4 ASJ exome

AF:

0.0000467

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.0000578

GnomAD4 genome

AF:

0.0000603

AC:

AN:

149164

Hom.:

Cov.:

AF XY:

0.0000549

AC XY:

AN XY:

72878

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.000398

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000806

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1276C>T (p.R426W) alteration is located in exon 11 (coding exon 10) of the KLC2 gene. This alteration results from a C to T substitution at nucleotide position 1276, causing the arginine (R) at amino acid position 426 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;T;.;T;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.93

D;.;D;.;.;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.7

L;L;.;L;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D

REVEL

Uncertain

0.56

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

0.49

MutPred

0.43

Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);.;Loss of disorder (P = 0.0245);.;.;

MVP

0.70

MPC

1.4

ClinPred

0.55

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.66

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