2-112738875-C-T

Position:

• chr2-112738875-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152515.5(CKAP2L):​c.2186G>A​(p.Arg729His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,962 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R729C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (12 hom.)
• Consequence: CKAP2L NM_152515.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79

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]

NT5DC4 (HGNC:27678): (5'-nucleotidase domain containing 4) Predicted to enable 5'-nucleotidase activity. Predicted to be involved in dephosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

CKAP2L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006461948).
• BP6: Variant 2-112738875-C-T is Benign according to our data. Variant chr2-112738875-C-T is described in ClinVar as [Benign]. Clinvar id is 785850.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00808 (1231/152296) while in subpopulation AFR AF= 0.0273 (1135/41570). AF 95% confidence interval is 0.026. There are 21 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CKAP2L	NM_152515.5	c.2186G>A	p.Arg729His	missense_variant	9/9	ENST00000302450.11	NP_689728.3
NT5DC4	NM_001393655.1	c.1345-38C>T		intron_variant		ENST00000688554.1	NP_001380584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CKAP2L	ENST00000302450.11	c.2186G>A	p.Arg729His	missense_variant	9/9	1	NM_152515.5	ENSP00000305204.6
NT5DC4	ENST00000688554.1	c.1345-38C>T		intron_variant			NM_001393655.1	ENSP00000509504.1

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152178 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00216 AC: 544 AN: 251422 Hom.: 7 AF XY: 0.00154 AC XY: 209 AN XY: 135880

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000866 AC: 1266 AN: 1461666 Hom.: 12 Cov.: 31 AF XY: 0.000736 AC XY: 535 AN XY: 727152

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00808 AC: 1231 AN: 152296 Hom.: 21 Cov.: 32 AF XY: 0.00822 AC XY: 612 AN XY: 74470

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00147 Hom.: 3

Bravo AF: 0.00910

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00273 AC: 332

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.52
MPC		0.40
ClinPred		0.034	T
GERP RS		5.5
Varity_R		0.14
gMVP		0.53

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: rs35691553; hg19: chr2-113496452;