Genetic Variant NM_001252102.2:c.4459G>A (chr1-200975654-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001252102.2(KIF21B):c.4459G>A(p.Glu1487Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KIF21B
NM_001252102.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.93

Variant links:

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]

KIF21B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
KIF21B	NM_001252102.2 link	c.4459G>A	p.Glu1487Lys	missense_variant	Exon 33 of 35	ENST00000461742.7	NP_001239031.1	O75037-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KIF21B	ENST00000461742.7 link	c.4459G>A	p.Glu1487Lys	missense_variant	Exon 33 of 35	1	NM_001252102.2	ENSP00000433808.1	O75037-4
KIF21B	ENST00000422435.2 link	c.4459G>A	p.Glu1487Lys	missense_variant	Exon 33 of 35	1		ENSP00000411831.2	O75037-1
KIF21B	ENST00000332129.6 link	c.4420G>A	p.Glu1474Lys	missense_variant	Exon 32 of 34	1		ENSP00000328494.2	O75037-2
KIF21B	ENST00000360529.9 link	c.4420G>A	p.Glu1474Lys	missense_variant	Exon 32 of 34	1		ENSP00000353724.5	O75037-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247942

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457968

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4420G>A (p.E1474K) alteration is located in exon 32 (coding exon 32) of the KIF21B gene. This alteration results from a G to A substitution at nucleotide position 4420, causing the glutamic acid (E) at amino acid position 1474 to be replaced by a lysine (K). 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

0.10

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

.;.;.;T

Eigen

Benign

-0.042

Eigen_PC

Benign

0.011

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.1

.;M;.;M

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.024

D;D;D;D

Sift4G

Uncertain

0.053

T;T;T;T

Polyphen

0.23

B;.;.;B

Vest4

0.65

MutPred

0.44

.;Gain of methylation at E1487 (P = 0.007);.;Gain of methylation at E1487 (P = 0.007);

MVP

0.64

MPC

0.66

ClinPred

0.90

GERP RS

4.8

Varity_R

0.22

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over