NM_152515.5:c.1123A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152515.5(CKAP2L):​c.1123A>G​(p.Ile375Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,614,134 control chromosomes in the GnomAD database, including 733,694 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68750 hom., cov: 31)
  • Exomes 𝑓: 0.95 (664944 hom.)
• Consequence: CKAP2L NM_152515.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.539236E-7).
• BP6: Variant 2-112756248-T-C is Benign according to our data. Variant chr2-112756248-T-C is described in ClinVar as [Benign]. Clinvar id is 1209748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKAP2L	NM_152515.5	c.1123A>G	p.Ile375Val	missense_variant	Exon 4 of 9	ENST00000302450.11	NP_689728.3
CKAP2L	NM_001304361.2	c.628A>G	p.Ile210Val	missense_variant	Exon 4 of 9		NP_001291290.1
CKAP2L	XM_011510666.3	c.628A>G	p.Ile210Val	missense_variant	Exon 3 of 8		XP_011508968.1
CKAP2L	NR_130712.2	n.490-114A>G		intron_variant	Intron 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKAP2L	ENST00000302450.11	c.1123A>G	p.Ile375Val	missense_variant	Exon 4 of 9	1	NM_152515.5	ENSP00000305204.6
CKAP2L	ENST00000435431.5	n.479-114A>G		intron_variant	Intron 4 of 9	2		ENSP00000414834.1
CKAP2L	ENST00000474331.1	n.-174A>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144581 AN: 152164 Hom.: 68703 Cov.: 31

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.981

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.939

GnomAD2 exomes AF: 0.963 AC: 242007 AN: 251422 AF XY: 0.962

Gnomad AFR exome AF: 0.926

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.960

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.952

Gnomad OTH exome AF: 0.959

GnomAD4 exome AF: 0.954 AC: 1394133 AN: 1461852 Hom.: 664944 Cov.: 64 AF XY: 0.954 AC XY: 694082 AN XY: 727234

African (AFR) AF: 0.924 AC: 30927 AN: 33480

American (AMR) AF: 0.970 AC: 43401 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 25148 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39691 AN: 39696

South Asian (SAS) AF: 0.977 AC: 84298 AN: 86256

European-Finnish (FIN) AF: 0.978 AC: 52265 AN: 53414

Middle Eastern (MID) AF: 0.954 AC: 5503 AN: 5768

European-Non Finnish (NFE) AF: 0.949 AC: 1055298 AN: 1111988

Other (OTH) AF: 0.954 AC: 57602 AN: 60392

GnomAD4 genome AF: 0.950 AC: 144684 AN: 152282 Hom.: 68750 Cov.: 31 AF XY: 0.952 AC XY: 70863 AN XY: 74458

African (AFR) AF: 0.928 AC: 38540 AN: 41546

American (AMR) AF: 0.961 AC: 14707 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3333 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5187 AN: 5188

South Asian (SAS) AF: 0.977 AC: 4710 AN: 4820

European-Finnish (FIN) AF: 0.981 AC: 10406 AN: 10608

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.950 AC: 64630 AN: 68032

Other (OTH) AF: 0.940 AC: 1989 AN: 2116

Alfa AF: 0.950 Hom.: 253385

Bravo AF: 0.947

TwinsUK AF: 0.951 AC: 3527

ALSPAC AF: 0.944 AC: 3639

ESP6500AA AF: 0.926 AC: 4081

ESP6500EA AF: 0.947 AC: 8147

ExAC AF: 0.962 AC: 116825

Asia WGS AF: 0.991 AC: 3446 AN: 3478

EpiCase AF: 0.952

EpiControl AF: 0.946

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Filippi syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

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	0.066
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0010
DANN	Benign	0.21
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		-2.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.050
Sift	Benign	0.41	T
Sift4G	Benign	0.59	T
Polyphen		0.0020	B
Vest4		0.0080
MPC		0.050
ClinPred		0.0045	T
GERP RS		-7.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
gMVP		0.039
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV107397841; COSMIC: COSV107397841;