Variant 11-66262157-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000394067.7(KLC2):c.494A>G(p.Asp165Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KLC2
ENST00000394067.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.14

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:

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.494A>G	p.Asp165Gly	missense_variant	4/16	ENST00000394067.7	NP_001305663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLC2	ENST00000394067.7 linkuse as main transcript	c.494A>G	p.Asp165Gly	missense_variant	4/16	1	NM_001318734.2	ENSP00000377631	P1	Q9H0B6-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251384

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135864

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461178

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2023

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. This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 165 of the KLC2 protein (p.Asp165Gly). This variant is present in population databases (rs762744349, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KLC2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;T;.;T;T;T;T;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;T;.;D;.;D;D;D;.;D

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.46

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.8

M;.;M;.;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.025

D;D;D;D;D;D;T;T;D;D

Sift4G

Benign

0.18

T;D;T;T;T;T;T;T;T;D

Polyphen

0.80

P;.;P;.;P;D;.;.;.;D

Vest4

0.93

MutPred

0.46

Gain of methylation at K161 (P = 0.0955);Gain of methylation at K161 (P = 0.0955);Gain of methylation at K161 (P = 0.0955);.;Gain of methylation at K161 (P = 0.0955);Gain of methylation at K161 (P = 0.0955);.;Gain of methylation at K161 (P = 0.0955);.;.;

MVP

0.87

MPC

0.85

ClinPred

0.62

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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