rs1553442237

Variant names:

• chr2-112756885-ACATTTACCATTTCCTTGATCTGTTAACTGCTGCTTTGTAGTTTTCAATTGCTCTATATTAAGTGACCCCACAGGTTTTCTTGACAGTTCTCCTGTTGTGGACGATCCAGCTTCACACTGTTGAAAACTCTTGCTAGAAGGCTTAGAGTATGGGTTAGAAGAAACACATTCTGAAGTCAGCCTTTTGCCCAGAAGTTTTGGTGGCTCCAACTTCGGCTTCTGGGACCCTGCAGTATTAGGTGGTCTGGGCTGGAGTTTAATGCTGATGGACCTTTTAGGTTTGACAGGCAAAACAACATGGTTGGTAACATCATTTTTGGGTCTAATAGT-A
• rs1553442237
• NM_152515.5:c.157_485del

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001304361.2(CKAP2L):​c.-280-59_-11del variant causes a splice acceptor, splice region, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CKAP2L NM_001304361.2 splice_acceptor, splice_region, 5_prime_UTR, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

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]

CKAP2L Gene-Disease associations (from GenCC):

• Filippi syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.67642 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 2-112756885-ACATTTACCATTTCCTTGATCTGTTAACTGCTGCTTTGTAGTTTTCAATTGCTCTATATTAAGTGACCCCACAGGTTTTCTTGACAGTTCTCCTGTTGTGGACGATCCAGCTTCACACTGTTGAAAACTCTTGCTAGAAGGCTTAGAGTATGGGTTAGAAGAAACACATTCTGAAGTCAGCCTTTTGCCCAGAAGTTTTGGTGGCTCCAACTTCGGCTTCTGGGACCCTGCAGTATTAGGTGGTCTGGGCTGGAGTTTAATGCTGATGGACCTTTTAGGTTTGACAGGCAAAACAACATGGTTGGTAACATCATTTTTGGGTCTAATAGT-A is Pathogenic according to our data. Variant chr2-112756885-ACATTTACCATTTCCTTGATCTGTTAACTGCTGCTTTGTAGTTTTCAATTGCTCTATATTAAGTGACCCCACAGGTTTTCTTGACAGTTCTCCTGTTGTGGACGATCCAGCTTCACACTGTTGAAAACTCTTGCTAGAAGGCTTAGAGTATGGGTTAGAAGAAACACATTCTGAAGTCAGCCTTTTGCCCAGAAGTTTTGGTGGCTCCAACTTCGGCTTCTGGGACCCTGCAGTATTAGGTGGTCTGGGCTGGAGTTTAATGCTGATGGACCTTTTAGGTTTGACAGGCAAAACAACATGGTTGGTAACATCATTTTTGGGTCTAATAGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 162388.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304361.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKAP2L	NM_152515.5	MANE Select	c.157_485del	p.Thr53TyrfsTer6	frameshift splice_region	Exon 4 of 9	NP_689728.3
	CKAP2L	NM_001304361.2		c.-280-59_-11del		splice_region	Exon 4 of 9	NP_001291290.1	Q8IYA6-3
	CKAP2L	NM_001304361.2		c.-280-59_-11del		splice_acceptor splice_region 5_prime_UTR intron	Exon 4 of 9	NP_001291290.1	Q8IYA6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKAP2L	ENST00000302450.11	TSL:1 MANE Select	c.157_485del	p.Thr53TyrfsTer6	frameshift splice_region	Exon 4 of 9	ENSP00000305204.6	Q8IYA6-1
	CKAP2L	ENST00000937152.1		c.157_485del	p.Thr53TyrfsTer6	frameshift splice_region	Exon 4 of 9	ENSP00000607211.1
	CKAP2L	ENST00000937153.1		c.157_485del	p.Thr53TyrfsTer6	frameshift splice_region	Exon 4 of 8	ENSP00000607212.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Filippi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=15/185	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553442237; hg19: chr2-113514462;