chr1-200981053-C-T

Position:

• chr1-200981053-C-T

Variant summary

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

The NM_001252102.2(KIF21B):​c.3886G>A​(p.Ala1296Thr) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF21B NM_001252102.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

KIF21B (HGNC:29442): (kinesin family member 21B) This gene encodes a member of the kinesin superfamily. Kinesins are ATP-dependent microtubule-based motor proteins that are involved in the intracellular transport of membranous organelles. Single nucleotide polymorphisms in this gene are associated with inflammatory bowel disease and multiple sclerosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

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
KIF21B	NM_001252102.2	c.3886G>A	p.Ala1296Thr	missense_variant	29/35	ENST00000461742.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF21B	ENST00000461742.7	c.3886G>A	p.Ala1296Thr	missense_variant	29/35	1	NM_001252102.2	P3
KIF21B	ENST00000422435.2	c.3886G>A	p.Ala1296Thr	missense_variant	29/35	1
KIF21B	ENST00000332129.6	c.3847G>A	p.Ala1283Thr	missense_variant	28/34	1
KIF21B	ENST00000360529.9	c.3847G>A	p.Ala1283Thr	missense_variant	28/34	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Invitae

Dec 20, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1283 of the KIF21B protein (p.Ala1283Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF21B-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KIF21B protein function with a negative predictive value of 80%. 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	0.16
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.043	.;.;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.97	.;L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.043	D;D;D;D
Sift4G	Benign	0.32	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.69
MutPred		0.26		.;Gain of phosphorylation at A1296 (P = 0.0267);.;Gain of phosphorylation at A1296 (P = 0.0267);
MVP		0.46
MPC		1.4
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.34

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: rs1655878067; hg19: chr1-200950181;