rs727502804

Variant names:

• chr2-112756619-CT-C
• rs727502804
• NM_152515.5:c.751delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_152515.5(CKAP2L):​c.751delA​(p.Ser251AlafsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CKAP2L NM_152515.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.318
• 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 2-112756619-CT-C is Pathogenic according to our data. Variant chr2-112756619-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162387.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152515.5. 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.751delA	p.Ser251AlafsTer6	frameshift	Exon 4 of 9	NP_689728.3
	CKAP2L	NM_001304361.2		c.256delA	p.Ser86AlafsTer6	frameshift	Exon 4 of 9	NP_001291290.1	Q8IYA6-3
	CKAP2L	NR_130712.2		n.489+273delA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKAP2L	ENST00000302450.11	TSL:1 MANE Select	c.751delA	p.Ser251AlafsTer6	frameshift	Exon 4 of 9	ENSP00000305204.6	Q8IYA6-1
	CKAP2L	ENST00000937152.1		c.751delA	p.Ser251AlafsTer6	frameshift	Exon 4 of 9	ENSP00000607211.1
	CKAP2L	ENST00000937153.1		c.751delA	p.Ser251AlafsTer6	frameshift	Exon 4 of 8	ENSP00000607212.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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		0.32
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727502804; hg19: chr2-113514196;