dbSNP rs587777570: KIF5C:p.Glu237Lys (chr2-148947018-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_004522.3(KIF5C):c.709G>A(p.Glu237Lys) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF5C
NM_004522.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

KIF5C (HGNC:6325): (kinesin family member 5C) The protein encoded by this gene is a kinesin heavy chain subunit involved in the transport of cargo within the central nervous system. The encoded protein, which acts as a tetramer by associating with another heavy chain and two light chains, interacts with protein kinase CK2. Mutations in this gene have been associated with complex cortical dysplasia with other brain malformations-2. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Jul 2015]

KIF5C links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 2-148947018-G-A is Pathogenic according to our data. Variant chr2-148947018-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-148947018-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-148947018-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5C	NM_004522.3 link	c.709G>A	p.Glu237Lys	missense_variant	Exon 8 of 26	ENST00000435030.6	NP_004513.1	O60282-1Q59GB8
KIF5C	XM_017004062.2 link	c.709G>A	p.Glu237Lys	missense_variant	Exon 8 of 26		XP_016859551.1	O60282-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5C	ENST00000435030.6 link	c.709G>A	p.Glu237Lys	missense_variant	Exon 8 of 26	1	NM_004522.3	ENSP00000393379.1		O60282-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725094

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 2

Pathogenic:9Other:1

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Missense variant c.709G>A in Exon 8 of the KIF5C gene that results in the amino acid substitution p.Glu237Lys was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID:140740]. The observed variation has previosuly been reported for complex cortical dysplasia with other brain malformations-2. Well-established functional studies show a deleterious effect by Willemsen, Marjolein H., et al., 2014. For these reasons this variant has been classified as Pathogenic. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Pathogenic, for Cortical dysplasia, complex, with other brain malformations 2, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. located in the kinesin motor domain and microtubule-binding region (http://www.uniprot.org/uniprot/O60282#family_and_domains). PS3 => Well-established functional studies show a deleterious effect (PMID:24812067). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:29048727) (PMID:23033978). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23033978) (PMID:29048727). -

Jul 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 23, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

PS2_moderate, PM1_supporting, PM2_supporting, PP2, PP3 -

Oct 04, 2023

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory de novo: in an 18-year-old female with intellectual disability, seizure disorder, long face, microcephaly; in a 7-year-old male with global delays, seizures, retained baby teeth, autism, cortical dysplasia, aggression, poor balance, strabismus -

Jun 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KIF5C c.709G>A (p.Glu237Lys) results in a conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243890 control chromosomes (gnomAD). c.709G>A has been reported in the literature in individuals affected with Complex Cortical Dysplasia, microcephaly, developmental disorders, and seizures, including several de novo occurrences (e.g., deLigt_2012, Michels_2017, vanderVen_2021, Duan_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35231114, 29048727, 23033978, 34490615). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Additionally, another missense variant affecting the same codon, c.710A>T (p.E237V), has been identified in four siblings affected with severe malformations of cortical development and microcephaly, and experimental studies found the variant results in complete absence of detectable ATP hydrolysis and protein mislocalization (PMID: 23603762). Based on the evidence outlined above, the variant was classified as pathogenic. -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 02-20-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Pathogenic:3

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF5C: PM2, PM5, PM6, PP2, PP3, PS3:Supporting, PS4:Supporting -

Jul 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 24812067); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23033978, 28191890, 29671837, 34490615, 26384676, 28867141, 28135719, 29048727, 26633545, 31101064, 31618753, 32562872, 31785789, 37486637, 33057194, 36122673, 35982159, 35231114, 24812067) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.65

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.82

Gain of MoRF binding (P = 0.0204);

MVP

0.91

MPC

3.1

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.99

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