12-39332404-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_001173464.2(KIF21A):c.2861G>A(p.Arg954Gln) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R954W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KIF21A
NM_001173464.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.62

Publications

17 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Laboratory for Molecular Medicine
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: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001173464.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-39332405-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-39332404-C-T is Pathogenic according to our data. Variant chr12-39332404-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF21A	NM_001173464.2 link	c.2861G>A	p.Arg954Gln	missense_variant	Exon 21 of 38	ENST00000361418.10	NP_001166935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF21A	ENST00000361418.10 link	c.2861G>A	p.Arg954Gln	missense_variant	Exon 21 of 38	1	NM_001173464.2	ENSP00000354878.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1

Pathogenic:2

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Fibrosis of extraocular muscles, congenital, 3b

Pathogenic:1

Mar 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:1

Jun 09, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 23336411, 21042561, 14595441, 18332320, 15747768)

Abnormality of eye movement

Pathogenic:1

Jun 03, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM2, PM5, PP1, PP3

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;.;T;.;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

0.0

.;.;.;.;M;.

PhyloP100

7.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.0

.;D;D;D;D;D

Sift

Pathogenic

0.0

.;D;D;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D;D;D

Vest4

0.0

ClinPred

1.0

GERP RS

5.5

PromoterAI

0.0068

Neutral

(source)

Varity_R

0.87

gMVP

0.62

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.66

Position offset: -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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over