11-66258814-G-A

Position:

• chr11-66258814-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000394067.7(KLC2):​c.220G>A​(p.Glu74Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLC2 ENST00000394067.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLC2	NM_001318734.2	c.220G>A	p.Glu74Lys	missense_variant	2/16	ENST00000394067.7	NP_001305663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLC2	ENST00000394067.7	c.220G>A	p.Glu74Lys	missense_variant	2/16	1	NM_001318734.2	ENSP00000377631	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 27, 2023

The c.220G>A (p.E74K) alteration is located in exon 2 (coding exon 1) of the KLC2 gene. This alteration results from a G to A substitution at nucleotide position 220, causing the glutamic acid (E) at amino acid position 74 to be replaced by a lysine (K). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;T;D;.;T;.;T;T;T;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;D;D;D;.
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.3	.;M;.;.;M;M;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;D;D;D;T;D;D;T;D;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;T;D;D;T;D;T
Polyphen		1.0	.;D;.;.;D;.;D;D;.;.;.
Vest4		0.84, 0.81, 0.75, 0.87, 0.78
MutPred		0.81		Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);Gain of ubiquitination at E74 (P = 0.0211);
MVP		0.73
MPC		1.5
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.78
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr11-66026285; COSMIC: COSV57582199; COSMIC: COSV57582199;