chr11-66261916-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001318734.2(KLC2):ā€‹c.403C>Gā€‹(p.Gln135Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

KLC2
NM_001318734.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.65
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06580135).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KLC2NM_001318734.2 linkuse as main transcriptc.403C>G p.Gln135Glu missense_variant 3/16 ENST00000394067.7 NP_001305663.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLC2ENST00000394067.7 linkuse as main transcriptc.403C>G p.Gln135Glu missense_variant 3/161 NM_001318734.2 ENSP00000377631 P1Q9H0B6-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
251228
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.000617
Gnomad AMR exome
AF:
0.0000579
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000657
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152326
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.000409
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:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000755
Hom.:
0
Bravo
AF:
0.000234
ESP6500AA
AF:
0.000682
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 19, 2022This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 135 of the KLC2 protein (p.Gln135Glu). This variant is present in population databases (rs150052320, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KLC2-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.46
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Benign
0.044
T;T;.;T;T;T;T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.94
D;D;D;.;.;D;D
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.066
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.69
N;.;.;N;N;.;.
MutationTaster
Benign
1.0
D;D;D;N;N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.28
N;N;N;N;N;N;N
REVEL
Benign
0.093
Sift
Benign
0.14
T;D;D;T;T;T;D
Sift4G
Benign
0.15
T;T;T;T;T;T;T
Polyphen
0.0010
B;.;.;B;B;B;.
Vest4
0.32
MVP
0.52
MPC
0.58
ClinPred
0.081
T
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.095
gMVP
0.22

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.

Other links and lift over

dbSNP: rs150052320; hg19: chr11-66029387; API