Genetic Variant NM_001173464.2:c.84C>G (chr12-39370222-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001173464.2(KIF21A):c.84C>G(p.Cys28Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C28R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KIF21A
NM_001173464.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.80

Publications

9 publications found

Variant links:

Genes affected

KIF21A (HGNC:19349): (kinesin family member 21A) This gene encodes a member of the KIF4 subfamily of kinesin-like motor proteins. The encoded protein is characterized by an N-terminal motor domain a coiled-coil stalk domain and a C-terminal WD-40 repeat domain. This protein may be involved in microtubule dependent transport. Mutations in this gene are the cause of congenital fibrosis of extraocular muscles-1. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

KIF21A Gene-Disease associations (from GenCC):

congenital fibrosis of extraocular muscles
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
congenital fibrosis of extraocular muscles type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
arthrogryposis multiplex congenita
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
fibrosis of extraocular muscles, congenital, 3b
Inheritance: AD Classification: LIMITED Submitted by: G2P

KIF21A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173464.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF21A	NM_001173464.2	MANE Select	c.84C>G	p.Cys28Trp	missense	Exon 2 of 38	NP_001166935.1	Q7Z4S6-1
KIF21A	NM_001378439.1		c.84C>G	p.Cys28Trp	missense	Exon 2 of 38	NP_001365368.1	Q7Z4S6-4
KIF21A	NM_001378440.1		c.84C>G	p.Cys28Trp	missense	Exon 2 of 37	NP_001365369.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF21A	ENST00000361418.10	TSL:1 MANE Select	c.84C>G	p.Cys28Trp	missense	Exon 2 of 38	ENSP00000354878.5	Q7Z4S6-1
KIF21A	ENST00000361961.7	TSL:1	c.84C>G	p.Cys28Trp	missense	Exon 2 of 37	ENSP00000354851.3	Q7Z4S6-2
KIF21A	ENST00000544797.6	TSL:1	c.84C>G	p.Cys28Trp	missense	Exon 2 of 34	ENSP00000445606.2	Q7Z4S6-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.1

PhyloP100

3.8

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-10

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.88

Gain of MoRF binding (P = 0.0486)

MVP

0.88

MPC

1.1

ClinPred

1.0

GERP RS

5.5

Varity_R

1.0

gMVP

0.83

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over