rs996589396

Positions:

• chr1-10261940-C-G
• chr1-10261940-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001365951.3(KIF1B):​c.399C>G​(p.Asn133Lys) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.36

Genes affected

KIF1B (HGNC:16636): (kinesin family member 1B) Predicted to enable microtubule binding activity and plus-end-directed microtubule motor activity. Predicted to be involved in chemical synaptic transmission; dense core granule cytoskeletal transport; and vesicle-mediated transport. Predicted to act upstream of or within mitochondrion transport along microtubule. Predicted to be located in cytoplasmic vesicle membrane and neuron projection. Predicted to be part of kinesin complex. Predicted to be active in several cellular components, including axon; dendrite; and microtubule. Implicated in Charcot-Marie-Tooth disease type 2A1; carcinoma (multiple); multiple sclerosis; neuroblastoma; and pheochromocytoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1B. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 5.2436 (greater than threshold 3.09). GenCC has associacion of gene with pheochromocytoma, neuroblastoma, susceptibility to, 1, hereditary pheochromocytoma-paraganglioma, Charcot-Marie-Tooth disease type 2A1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13711867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.399C>G	p.Asn133Lys	missense_variant	5/49	ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.399C>G	p.Asn133Lys	missense_variant	5/49		NM_001365951.3	ENSP00000502065	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The p.N133K variant (also known as c.399C>G), located in coding exon 4 of the KIF1B gene, results from a C to G substitution at nucleotide position 399. The asparagine at codon 133 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2018

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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KIF1B-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 133 of the KIF1B protein (p.Asn133Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	.;.;D;.;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	.;T;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.27	N;N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;.;.
REVEL	Benign	0.15
Sift	Benign	0.14	T;D;D;T;T;.;.
Sift4G	Benign	0.25	T;T;T;T;T;T;T
Polyphen		0.033	B;B;B;B;.;B;.
Vest4		0.28
MutPred		0.42		Gain of methylation at N133 (P = 0.0053);Gain of methylation at N133 (P = 0.0053);Gain of methylation at N133 (P = 0.0053);Gain of methylation at N133 (P = 0.0053);Gain of methylation at N133 (P = 0.0053);Gain of methylation at N133 (P = 0.0053);Gain of methylation at N133 (P = 0.0053);
MVP		0.54
MPC		1.0
ClinPred		0.74	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.57

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: rs996589396; hg19: chr1-10321998;