Genetic Variant NM_152515.5:c.2084G>A (chr2-112738977-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152515.5(CKAP2L):c.2084G>A(p.Arg695Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,184 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 116 hom. )

Consequence

CKAP2L
NM_152515.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.276

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033853948).

BP6

Variant 2-112738977-C-T is Benign according to our data. Variant chr2-112738977-C-T is described in ClinVar as Benign. ClinVar VariationId is 790255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00833 (1268/152310) while in subpopulation NFE AF = 0.0133 (907/68038). AF 95% confidence interval is 0.0126. There are 9 homozygotes in GnomAd4. There are 593 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 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.2084G>A	p.Arg695Gln	missense	Exon 9 of 9	NP_689728.3
NT5DC4	NM_001393655.1	MANE Select	c.*41C>T		3_prime_UTR	Exon 17 of 17	NP_001380584.1	Q86YG4-2
CKAP2L	NM_001304361.2		c.1589G>A	p.Arg530Gln	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.2084G>A	p.Arg695Gln	missense	Exon 9 of 9	ENSP00000305204.6	Q8IYA6-1
NT5DC4	ENST00000688554.1	MANE Select	c.*41C>T		3_prime_UTR	Exon 17 of 17	ENSP00000509504.1	Q86YG4-2
NT5DC4	ENST00000327581.4	TSL:1	c.1249-3435C>T		intron	N/A	ENSP00000330247.4	Q86YG4-1

Frequencies

GnomAD3 genomes

AF:

0.00833

AC:

1268

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00878

AC:

2208

AN:

251462

AF XY:

0.00871

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00306

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0113

AC:

16482

AN:

1461874

Hom.:

116

Cov.:

AF XY:

0.0109

AC XY:

7963

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33480

American (AMR)

AF:

0.00349

AC:

156

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00478

AC:

125

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86258

European-Finnish (FIN)

AF:

0.0173

AC:

925

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0131

AC:

14574

AN:

1111994

Other (OTH)

AF:

0.00899

AC:

543

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

900

1799

2699

3598

4498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.00833

AC:

1268

AN:

152310

Hom.:

Cov.:

AF XY:

0.00796

AC XY:

593

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41574

American (AMR)

AF:

0.00432

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0133

AC:

907

AN:

68038

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0102

Hom.:

Bravo

AF:

0.00714

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00897

AC:

1089

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0045

Eigen

Benign

0.11

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

PhyloP100

0.28

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.31

REVEL

Benign

0.11

Sift

Benign

0.095

Sift4G

Benign

0.098

Polyphen

0.93

Vest4

0.081

MVP

0.25

MPC

0.14

ClinPred

0.026

GERP RS

4.6

Varity_R

0.044

gMVP

0.21

Mutation Taster

=98/2

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

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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