chr2-112762530-T-C

Variant names:

• chr2-112762530-T-C
• rs35593767
• NM_152515.5:c.77A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_152515.5(CKAP2L):​c.77A>G​(p.Lys26Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000668 in 1,614,098 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: CKAP2L NM_152515.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.72

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010289341).
• BP6: Variant 2-112762530-T-C is Benign according to our data. Variant chr2-112762530-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421559.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr2-112762530-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00305 (464/152334) while in subpopulation AFR AF = 0.0105 (435/41580). AF 95% confidence interval is 0.00965. There are 5 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKAP2L	NM_152515.5	c.77A>G	p.Lys26Arg	missense_variant	Exon 2 of 9	ENST00000302450.11	NP_689728.3
CKAP2L	NM_001304361.2	c.-360A>G		5_prime_UTR_variant	Exon 2 of 9		NP_001291290.1
CKAP2L	XM_011510666.3	c.-391-1766A>G		intron_variant	Intron 1 of 7		XP_011508968.1
CKAP2L	NR_130712.2	n.88A>G		non_coding_transcript_exon_variant	Exon 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKAP2L	ENST00000302450.11	c.77A>G	p.Lys26Arg	missense_variant	Exon 2 of 9	1	NM_152515.5	ENSP00000305204.6

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 463 AN: 152216 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00105 AC: 265 AN: 251478 AF XY: 0.000817

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000421 AC: 615 AN: 1461764 Hom.: 4 Cov.: 30 AF XY: 0.000364 AC XY: 265 AN XY: 727186

African (AFR) AF: 0.0114 AC: 381 AN: 33478

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111906

Other (OTH) AF: 0.00114 AC: 69 AN: 60394

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152334 Hom.: 5 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74502

African (AFR) AF: 0.0105 AC: 435 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00116 Hom.: 2

Bravo AF: 0.00354

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CKAP2L: BS1 -

Jun 27, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The K26R variant in the CKAP2L gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. The NHLBI ESP Exome Sequencing Project reports that K26Rwas observed in 49/4406 alleles (1.11%) from individuals of African American ancestry, indicating itmay be a rare benign variant in this population. The variant was not present in the homozygous statewithin this population, though the 1000 Genomes Database reports K26R was observed once in thehomozygous state in approximately 600 individuals of African background (McVean et al., 2012). TheK26R variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. However, this substitution occurs at aposition that is conserved in mammals, and in silico analysis predicts this variant is probably damagingto the protein structure/function. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.39
MPC		0.34
ClinPred		0.034	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.33
Mutation Taster		=92/8	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

Publications

LitVar

Other links and lift over

dbSNP: rs35593767; hg19: chr2-113520107;