chr2-112756248-T-G

Variant names:

• chr2-112756248-T-G
• rs6731822
• NM_152515.5:c.1123A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152515.5(CKAP2L):​c.1123A>C​(p.Ile375Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I375V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CKAP2L NM_152515.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.57
• Publications: 35 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041383862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKAP2L	NM_152515.5	c.1123A>C	p.Ile375Leu	missense_variant	Exon 4 of 9	ENST00000302450.11	NP_689728.3
CKAP2L	NM_001304361.2	c.628A>C	p.Ile210Leu	missense_variant	Exon 4 of 9		NP_001291290.1
CKAP2L	XM_011510666.3	c.628A>C	p.Ile210Leu	missense_variant	Exon 3 of 8		XP_011508968.1
CKAP2L	NR_130712.2	n.490-114A>C		intron_variant	Intron 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKAP2L	ENST00000302450.11	c.1123A>C	p.Ile375Leu	missense_variant	Exon 4 of 9	1	NM_152515.5	ENSP00000305204.6
CKAP2L	ENST00000435431.5	n.479-114A>C		intron_variant	Intron 4 of 9	2		ENSP00000414834.1
CKAP2L	ENST00000474331.1	n.-174A>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251422 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000410 AC: 6 AN: 1461874 Hom.: 0 Cov.: 64 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0050
DANN	Benign	0.77
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-2.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.036
Sift	Benign	0.079	T
Sift4G	Benign	0.18	T
Polyphen		0.10	B
Vest4		0.085
MutPred		0.20		Loss of MoRF binding (P = 0.0987);
MVP		0.081
MPC		0.057
ClinPred		0.10	T
GERP RS		-7.9
Varity_R		0.040
gMVP		0.039
Mutation Taster		=98/2	polymorphism

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: rs6731822; hg19: chr2-113513825;