NM_001252102.2:c.4723G>T

Variant names:

• chr1-200974805-C-A
• NM_001252102.2:c.4723G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001252102.2(KIF21B):​c.4723G>T​(p.Asp1575Tyr) 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: KIF21B NM_001252102.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF21B	NM_001252102.2	c.4723G>T	p.Asp1575Tyr	missense_variant	Exon 34 of 35	ENST00000461742.7	NP_001239031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF21B	ENST00000461742.7	c.4723G>T	p.Asp1575Tyr	missense_variant	Exon 34 of 35	1	NM_001252102.2	ENSP00000433808.1
KIF21B	ENST00000422435.2	c.4723G>T	p.Asp1575Tyr	missense_variant	Exon 34 of 35	1		ENSP00000411831.2
KIF21B	ENST00000332129.6	c.4684G>T	p.Asp1562Tyr	missense_variant	Exon 33 of 34	1		ENSP00000328494.2
KIF21B	ENST00000360529.9	c.4684G>T	p.Asp1562Tyr	missense_variant	Exon 33 of 34	1		ENSP00000353724.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic intellectual disability Uncertain:1

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in KIF21B is predicted to replace aspartic acid with tyrosine at codon 1575, p.(Asp1575Tyr). The aspartic acid residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the WD repeat 6 in a region (amino acids 1574-1576) highly intolerant to missense variation. There is a large physicochemical difference between aspartic acid and tyrosine. This variant is absent from the population database gnomAD v4.1. To our knowledge, this variant is novel and has not been previously reported in the relevant scientific literature or databases. Computational evidence is uninformative for the missense substitution (REVEL = 0.30) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;.;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.83
MutPred		0.45		.;Gain of catalytic residue at P1579 (P = 0.0669);.;Gain of catalytic residue at P1579 (P = 0.0669);
MVP		0.40
MPC		1.4
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.78
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-200943933;