11-66265187-C-T

Position:

• chr11-66265187-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000394067.7(KLC2):​c.1286C>T​(p.Ala429Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A429T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLC2 ENST00000394067.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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-AS1 (HGNC:40934): (KLC2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16069779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLC2	NM_001318734.2	c.1286C>T	p.Ala429Val	missense_variant	11/16	ENST00000394067.7	NP_001305663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLC2	ENST00000394067.7	c.1286C>T	p.Ala429Val	missense_variant	11/16	1	NM_001318734.2	ENSP00000377631	P1
KLC2-AS1	ENST00000530805.1	n.349G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 429 of the KLC2 protein (p.Ala429Val). This variant is not present in population databases (gnomAD no frequency). 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. 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	0.072
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;T;.;T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.88	D;.;D;.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.2	L;L;.;L;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.080	T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.0030	B;B;.;B;.;B
Vest4		0.23
MutPred		0.25		Loss of disorder (P = 0.0892);Loss of disorder (P = 0.0892);.;Loss of disorder (P = 0.0892);.;.;
MVP		0.60
MPC		0.51
ClinPred		0.68	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.45

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

Other links and lift over

dbSNP: rs1339013119; hg19: chr11-66032658;