NM_001318734.2:c.1276C>T

Variant names:

• chr11-66265177-C-T
• rs774715084
• NM_001318734.2:c.1276C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001318734.2(KLC2):​c.1276C>T​(p.Arg426Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000289 in 1,487,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R426Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: KLC2 NM_001318734.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38813657).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318734.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC2	NM_001318734.2	MANE Select	c.1276C>T	p.Arg426Trp	missense	Exon 11 of 16	NP_001305663.1	Q9H0B6-1
	KLC2	NM_001134775.2		c.1276C>T	p.Arg426Trp	missense	Exon 11 of 16	NP_001128247.1	Q9H0B6-1
	KLC2	NM_001134776.2		c.1276C>T	p.Arg426Trp	missense	Exon 11 of 16	NP_001128248.1	Q9H0B6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC2	ENST00000394067.7	TSL:1 MANE Select	c.1276C>T	p.Arg426Trp	missense	Exon 11 of 16	ENSP00000377631.2	Q9H0B6-1
	KLC2	ENST00000316924.9	TSL:1	c.1276C>T	p.Arg426Trp	missense	Exon 11 of 16	ENSP00000314837.5	Q9H0B6-1
	KLC2	ENST00000917341.1		c.1276C>T	p.Arg426Trp	missense	Exon 11 of 16	ENSP00000587400.1

Frequencies

GnomAD3 genomes AF: 0.0000671 AC: 10 AN: 149028 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000465

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: 0.0000149

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251342 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000254 AC: 34 AN: 1338550 Hom.: 0 Cov.: 34 AF XY: 0.0000300 AC XY: 20 AN XY: 665684

African (AFR) AF: 0.0000339 AC: 1 AN: 29512

American (AMR) AF: 0.000172 AC: 7 AN: 40690

Ashkenazi Jewish (ASJ) AF: 0.0000467 AC: 1 AN: 21406

East Asian (EAS) AF: 0.00 AC: 0 AN: 28304

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5168

European-Non Finnish (NFE) AF: 0.0000203 AC: 21 AN: 1035076

Other (OTH) AF: 0.0000578 AC: 3 AN: 51872

GnomAD4 genome AF: 0.0000603 AC: 9 AN: 149164 Hom.: 0 Cov.: 33 AF XY: 0.0000549 AC XY: 4 AN XY: 72878

African (AFR) AF: 0.0000243 AC: 1 AN: 41122

American (AMR) AF: 0.000398 AC: 6 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4846

South Asian (SAS) AF: 0.00 AC: 0 AN: 4570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67004

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000806 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.43		Loss of disorder (P = 0.0245)
MVP		0.70
MPC		1.4
ClinPred		0.55	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.66
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs774715084; hg19: chr11-66032648; COSMIC: COSV57582947; COSMIC: COSV57582947;