chr2-112738876-G-A

Position:

chr2-112738876-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_152515.5(CKAP2L):c.2185C>T(p.Arg729Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00958 in 1,613,802 control chromosomes in the GnomAD database, including 120 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. R729H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0078 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 111 hom. )

Consequence

CKAP2L
NM_152515.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.05

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006101191).

BP6

Variant 2-112738876-G-A is Benign according to our data. Variant chr2-112738876-G-A is described in ClinVar as [Benign]. Clinvar id is 775177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-112738876-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0078 (1188/152240) while in subpopulation SAS AF= 0.0141 (68/4820). AF 95% confidence interval is 0.0114. There are 9 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CKAP2L	NM_152515.5 linkuse as main transcript	c.2185C>T	p.Arg729Cys	missense_variant	9/9	ENST00000302450.11
NT5DC4	NM_001393655.1 linkuse as main transcript	c.1345-37G>A		intron_variant		ENST00000688554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CKAP2L	ENST00000302450.11 linkuse as main transcript	c.2185C>T	p.Arg729Cys	missense_variant	9/9	1	NM_152515.5	P1	Q8IYA6-1
NT5DC4	ENST00000688554.1 linkuse as main transcript	c.1345-37G>A		intron_variant			NM_001393655.1

Frequencies

GnomAD3 genomes

AF:

0.00782

AC:

1189

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.00904

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00378

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.00932

AC:

2344

AN:

251408

Hom.:

AF XY:

0.0102

AC XY:

1386

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00619

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0180

Gnomad FIN exome

AF:

0.00462

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.00977

AC:

14276

AN:

1461562

Hom.:

111

Cov.:

AF XY:

0.0102

AC XY:

7426

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.00680

Gnomad4 ASJ exome

AF:

0.00586

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0181

Gnomad4 FIN exome

AF:

0.00569

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00859

GnomAD4 genome

AF:

0.00780

AC:

1188

AN:

152240

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00896

Gnomad4 ASJ

AF:

0.00952

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00378

Gnomad4 NFE

AF:

0.0112

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00760

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.00970

AC:

1178

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0127

EpiControl

AF:

0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

May 11, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.031

Polyphen

0.97

Vest4

0.23

MVP

0.22

MPC

0.34

ClinPred

0.051

GERP RS

4.6

Varity_R

0.38

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over