rs4837768

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018249.6(CDK5RAP2):c.4618G>C(p.Val1540Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 1,613,638 control chromosomes in the GnomAD database, including 462,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39807 hom., cov: 32)

Exomes 𝑓: 0.76 ( 423069 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.0720

Variant links:

Genes affected

CDK5RAP2 (HGNC:18672): (CDK5 regulatory subunit associated protein 2) This gene encodes a regulator of CDK5 (cyclin-dependent kinase 5) activity. The protein encoded by this gene is localized to the centrosome and Golgi complex, interacts with CDK5R1 and pericentrin (PCNT), plays a role in centriole engagement and microtubule nucleation, and has been linked to primary microcephaly and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

CDK5RAP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.204581E-7).

BP6

Variant 9-120408455-C-G is Benign according to our data. Variant chr9-120408455-C-G is described in ClinVar as [Benign]. Clinvar id is 21651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120408455-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 linkuse as main transcript	c.4618G>C	p.Val1540Leu	missense_variant	31/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9 linkuse as main transcript	c.4618G>C	p.Val1540Leu	missense_variant	31/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.717

AC:

109042

AN:

152000

Hom.:

39799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.584

Gnomad AMI

AF:

0.755

Gnomad AMR

AF:

0.806

Gnomad ASJ

AF:

0.736

Gnomad EAS

AF:

0.833

Gnomad SAS

AF:

0.824

Gnomad FIN

AF:

0.794

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.748

Gnomad OTH

AF:

0.735

GnomAD3 exomes

AF:

0.777

AC:

195229

AN:

251218

Hom.:

76578

AF XY:

0.778

AC XY:

105624

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.580

Gnomad AMR exome

AF:

0.883

Gnomad ASJ exome

AF:

0.742

Gnomad EAS exome

AF:

0.832

Gnomad SAS exome

AF:

0.825

Gnomad FIN exome

AF:

0.785

Gnomad NFE exome

AF:

0.753

Gnomad OTH exome

AF:

0.780

GnomAD4 exome

AF:

0.759

AC:

1109893

AN:

1461520

Hom.:

423069

Cov.:

AF XY:

0.761

AC XY:

553547

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.575

Gnomad4 AMR exome

AF:

0.875

Gnomad4 ASJ exome

AF:

0.739

Gnomad4 EAS exome

AF:

0.807

Gnomad4 SAS exome

AF:

0.823

Gnomad4 FIN exome

AF:

0.784

Gnomad4 NFE exome

AF:

0.753

Gnomad4 OTH exome

AF:

0.752

GnomAD4 genome

AF:

0.717

AC:

109098

AN:

152118

Hom.:

39807

Cov.:

AF XY:

0.721

AC XY:

53655

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.584

Gnomad4 AMR

AF:

0.806

Gnomad4 ASJ

AF:

0.736

Gnomad4 EAS

AF:

0.833

Gnomad4 SAS

AF:

0.823

Gnomad4 FIN

AF:

0.794

Gnomad4 NFE

AF:

0.748

Gnomad4 OTH

AF:

0.733

Alfa

AF:

0.744

Hom.:

31737

Bravo

AF:

0.715

TwinsUK

AF:

0.767

AC:

2843

ALSPAC

AF:

0.768

AC:

2958

ESP6500AA

AF:

0.584

AC:

2574

ESP6500EA

AF:

0.753

AC:

6473

ExAC

AF:

0.769

AC:

93364

Asia WGS

AF:

0.814

AC:

2833

AN:

3478

EpiCase

AF:

0.746

EpiControl

AF:

0.750

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 3, primary, autosomal recessive

Benign:3Other:1

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Primary Microcephaly, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.8

DANN

Benign

0.85

DEOGEN2

Benign

0.077

.;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.56

T;T;T;T;T

MetaRNN

Benign

8.2e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

.;N;N;.;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

0.64

.;N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.75

.;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.0060, 0.0, 0.10, 0.041

.;B;B;B;B

Vest4

0.078

MutPred

0.11

.;Loss of MoRF binding (P = 0.0907);Loss of MoRF binding (P = 0.0907);.;.;

MPC

0.079

ClinPred

0.0068

GERP RS

-0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.031

gMVP

0.062

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