chr1-200977260-A-G

Position:

• chr1-200977260-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000461742.7(KIF21B):​c.4277T>C​(p.Met1426Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF21B ENST00000461742.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13592187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF21B	NM_001252102.2	c.4277T>C	p.Met1426Thr	missense_variant	31/35	ENST00000461742.7	NP_001239031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF21B	ENST00000461742.7	c.4277T>C	p.Met1426Thr	missense_variant	31/35	1	NM_001252102.2	ENSP00000433808	P3
KIF21B	ENST00000422435.2	c.4277T>C	p.Met1426Thr	missense_variant	31/35	1		ENSP00000411831
KIF21B	ENST00000332129.6	c.4238T>C	p.Met1413Thr	missense_variant	30/34	1		ENSP00000328494
KIF21B	ENST00000360529.9	c.4238T>C	p.Met1413Thr	missense_variant	30/34	1		ENSP00000353724	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.4238T>C (p.M1413T) alteration is located in exon 30 (coding exon 30) of the KIF21B gene. This alteration results from a T to C substitution at nucleotide position 4238, causing the methionine (M) at amino acid position 1413 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.51
DEOGEN2	Benign	0.020	.;.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.20	.;N;.;N
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.33
MutPred		0.45		.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.13
MPC		0.58
ClinPred		0.30	T
GERP RS		2.6
Varity_R		0.057
gMVP		0.32

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: rs1655621303; hg19: chr1-200946388; COSMIC: COSV100144560;