rs727502805

Variant names:

• chr2-112756815-CTT-C
• rs727502805
• NM_152515.5:c.554_555delAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152515.5(CKAP2L):​c.554_555delAA​(p.Lys185ArgfsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000936 in 1,602,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CKAP2L NM_152515.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.79

Genes affected

CKAP2L (HGNC:26877): (cytoskeleton associated protein 2 like) The protein encoded by this gene is thought to be a mitotic spindle protein important to neural stem or progenitor cells. Mutations in this gene have been associated with spindle organization defects, including mitotic spindle defects, lagging chromosomes, and chromatin bridges. There is evidence that mutations in this gene are associated with Filippi syndrome, characterized by growth defects, microcephaly, intellectual disability, facial feature defects, and syndactyly. There is a pseudogene of this gene on chromosome 20. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-112756815-CTT-C is Pathogenic according to our data. Variant chr2-112756815-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 162389.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-112756815-CTT-C is described in Lovd as [Likely_pathogenic]. Variant chr2-112756815-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKAP2L	NM_152515.5	c.554_555delAA	p.Lys185ArgfsTer11	frameshift_variant	Exon 4 of 9	ENST00000302450.11	NP_689728.3
CKAP2L	NM_001304361.2	c.59_60delAA	p.Lys20ArgfsTer11	frameshift_variant	Exon 4 of 9		NP_001291290.1
CKAP2L	XM_011510666.3	c.59_60delAA	p.Lys20ArgfsTer11	frameshift_variant	Exon 3 of 8		XP_011508968.1
CKAP2L	NR_130712.2	n.489+76_489+77delAA		intron_variant	Intron 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKAP2L	ENST00000302450.11	c.554_555delAA	p.Lys185ArgfsTer11	frameshift_variant	Exon 4 of 9	1	NM_152515.5	ENSP00000305204.6
CKAP2L	ENST00000481732.5	n.515_516delAA		non_coding_transcript_exon_variant	Exon 4 of 4	4
CKAP2L	ENST00000435431.5	n.478+76_478+77delAA		intron_variant	Intron 4 of 9	2		ENSP00000414834.1
CKAP2L	ENST00000461876.5	n.*137_*138delAA		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000839 AC: 2 AN: 238322 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000690 AC: 10 AN: 1450056 Hom.: 0 AF XY: 0.00000832 AC XY: 6 AN XY: 721150

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in homozygous or apparent homozygous state in unrelated patients with Filippi syndrome in the literature, and not observed in homozygous state in controls (PMID: 38738944, 25439729); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33057194, 35982159, 28135719, 25439729, 28274275, 31785789, 38738944) -

Filippi syndrome Pathogenic:1

Nov 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs727502805; hg19: chr2-113514392;