Genetic Variant KIF23:p.Leu266His (chr15-69426090-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_001367805.3(KIF23):c.797T>A(p.Leu266His) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L266L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

KIF23
NM_001367805.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.82

Publications

3 publications found

Variant links:

Genes affected

KIF23 (HGNC:6392): (kinesin family member 23) The protein encoded by this gene is a member of kinesin-like protein family. This family includes microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. This protein has been shown to cross-bridge antiparallel microtubules and drive microtubule movement in vitro. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

KIF23 links:

KIF23-AS1 (HGNC:27075): (KIF23 and PAQR5 antisense RNA 1)

KIF23-AS1 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, 0.855

PP5

Variant 15-69426090-T-A is Pathogenic according to our data. Variant chr15-69426090-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402143.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367805.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF23	NM_001367805.3	MANE Select	c.797T>A	p.Leu266His	missense	Exon 9 of 24	NP_001354734.1
KIF23	NM_138555.4		c.755T>A	p.Leu252His	missense	Exon 8 of 23	NP_612565.1
KIF23	NM_001367804.2		c.755T>A	p.Leu252His	missense	Exon 8 of 22	NP_001354733.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF23	ENST00000679126.1	MANE Select	c.797T>A	p.Leu266His	missense	Exon 9 of 24	ENSP00000504770.1
KIF23	ENST00000260363.9	TSL:1	c.755T>A	p.Leu252His	missense	Exon 8 of 23	ENSP00000260363.4
KIF23	ENST00000352331.8	TSL:1	c.755T>A	p.Leu252His	missense	Exon 8 of 22	ENSP00000304978.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Microcephaly

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

KIF23 is predicted to interact with several genes previously associated with microcephaly

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.1

PhyloP100

7.8

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MutPred

0.60

Loss of stability (P = 0.0036)

MVP

0.95

MPC

1.0

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over