rs587777570

Positions:

• chr2-148947018-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF5C. . Gene score misZ 4.0539 (greater than the threshold 3.09). Trascript score misZ 3.6179 (greater than threshold 3.09). GenCC has associacion of gene with complex cortical dysplasia with other brain malformations 2.
• 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/exons	MANE	Protein	UniProt
KIF5C	NM_004522.3	c.709G>A	p.Glu237Lys	missense_variant	8/26	ENST00000435030.6	NP_004513.1
KIF5C	XM_017004062.2	c.709G>A	p.Glu237Lys	missense_variant	8/26		XP_016859551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF5C	ENST00000435030.6	c.709G>A	p.Glu237Lys	missense_variant	8/26	1	NM_004522.3	ENSP00000393379.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457786 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 2 Pathogenic:9 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2014	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Pathogenic, criteria provided, single submitter	literature only	Institute of Human Genetics, University of Leipzig Medical Center	Dec 12, 2024	PS2_moderate, PM1_supporting, PM2_supporting, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Oct 04, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	KIF5C: PM2, PM5, PM6, PP2, PP3, PS3:Supporting, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.65	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.82		Gain of MoRF binding (P = 0.0204);
MVP		0.91
MPC		3.1
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs587777570; hg19: chr2-149803532;