NM_001252102.2:c.4379C>T

Variant names:

• chr1-200976840-G-A
• rs371235023
• NM_001252102.2:c.4379C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001252102.2(KIF21B):​c.4379C>T​(p.Thr1460Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: KIF21B NM_001252102.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• BS2: High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF21B	NM_001252102.2	c.4379C>T	p.Thr1460Met	missense_variant	Exon 32 of 35	ENST00000461742.7	NP_001239031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF21B	ENST00000461742.7	c.4379C>T	p.Thr1460Met	missense_variant	Exon 32 of 35	1	NM_001252102.2	ENSP00000433808.1
KIF21B	ENST00000422435.2	c.4379C>T	p.Thr1460Met	missense_variant	Exon 32 of 35	1		ENSP00000411831.2
KIF21B	ENST00000332129.6	c.4340C>T	p.Thr1447Met	missense_variant	Exon 31 of 34	1		ENSP00000328494.2
KIF21B	ENST00000360529.9	c.4340C>T	p.Thr1447Met	missense_variant	Exon 31 of 34	1		ENSP00000353724.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250694 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135560

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461388 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 726926

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4340C>T (p.T1447M) alteration is located in exon 31 (coding exon 31) of the KIF21B gene. This alteration results from a C to T substitution at nucleotide position 4340, causing the threonine (T) at amino acid position 1447 to be replaced by a methionine (M). 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	Benign	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	.;.;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.5	.;M;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.81
MVP		0.69
MPC		1.4
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.26
gMVP		0.54

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: rs371235023; hg19: chr1-200945968;