11-66262159-G-A

Position:

• chr11-66262159-G-A

Variant summary

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

The NM_001318734.2(KLC2):​c.496G>A​(p.Asp166Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D166V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLC2 NM_001318734.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86

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]

ACMG classification

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	UniProt
KLC2	NM_001318734.2	c.496G>A	p.Asp166Asn	missense_variant	4/16	ENST00000394067.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLC2	ENST00000394067.7	c.496G>A	p.Asp166Asn	missense_variant	4/16	1	NM_001318734.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The c.496G>A (p.D166N) alteration is located in exon 4 (coding exon 3) of the KLC2 gene. This alteration results from a G to A substitution at nucleotide position 496, causing the aspartic acid (D) at amino acid position 166 to be replaced by an asparagine (N). 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	0.32
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.;T;.;T;T;T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.;D;D;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.49	T;D;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;D;D;N;D;D;D;N;N;D
REVEL	Benign	0.18
Sift	Benign	0.036	D;T;D;D;D;D;D;D;D;D
Sift4G	Benign	0.083	T;T;T;T;T;T;T;D;T;D
Polyphen		0.31	B;.;B;.;B;B;.;.;.;D
Vest4		0.86
MutPred		0.37		Gain of methylation at K161 (P = 0.1726);Gain of methylation at K161 (P = 0.1726);Gain of methylation at K161 (P = 0.1726);.;Gain of methylation at K161 (P = 0.1726);Gain of methylation at K161 (P = 0.1726);.;Gain of methylation at K161 (P = 0.1726);.;.;
MVP		0.75
MPC		1.4
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.38
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66029630;