Genetic Variant NM_152515.5:c.2186G>A (chr2-112738875-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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 Benign.

Frequency

Genomes: 𝑓 0.0081 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 12 hom. )

Consequence

CKAP2L
NM_152515.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.79

Publications

4 publications found

Variant links:

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 links:

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]

NT5DC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CKAP2L	NM_152515.5	MANE Select	c.2186G>A	p.Arg729His	missense	Exon 9 of 9	NP_689728.3
NT5DC4	NM_001393655.1	MANE Select	c.1345-38C>T		intron	N/A	NP_001380584.1	Q86YG4-2
CKAP2L	NM_001304361.2		c.1691G>A	p.Arg564His	missense	Exon 9 of 9	NP_001291290.1	Q8IYA6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CKAP2L	ENST00000302450.11	TSL:1 MANE Select	c.2186G>A	p.Arg729His	missense	Exon 9 of 9	ENSP00000305204.6	Q8IYA6-1
NT5DC4	ENST00000688554.1	MANE Select	c.1345-38C>T		intron	N/A	ENSP00000509504.1	Q86YG4-2
NT5DC4	ENST00000327581.4	TSL:1	c.1249-3537C>T		intron	N/A	ENSP00000330247.4	Q86YG4-1

Frequencies

GnomAD3 genomes

AF:

0.00807

AC:

1228

AN:

152178

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00216

AC:

544

AN:

251422

AF XY:

0.00154

show subpopulations

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 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.:

Cov.:

AF XY:

0.000736

AC XY:

535

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.0278

AC:

929

AN:

33466

American (AMR)

AF:

0.00163

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26132

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000105

AC:

117

AN:

1111818

Other (OTH)

AF:

0.00190

AC:

115

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00808

AC:

1231

AN:

152296

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

612

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0273

AC:

1135

AN:

41570

American (AMR)

AF:

0.00445

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00310

Hom.:

Bravo

AF:

0.00910

ESP6500AA

AF:

0.0277

AC:

122

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00273

AC:

332

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.8

PhyloP100

1.8

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.34

Sift

Uncertain

0.019

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.20

MVP

0.52

MPC

0.40

ClinPred

0.034

GERP RS

5.5

Varity_R

0.14

gMVP

0.53

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over