rs4836822

Positions:

chr9-120528758-C-G

Variant summary

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

The NM_018249.6(CDK5RAP2):c.865G>C(p.Glu289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,606,270 control chromosomes in the GnomAD database, including 661,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 55080 hom., cov: 32)

Exomes 𝑓: 0.91 ( 606530 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.64

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:

CDK5RAP2 (HGNC:):

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=7.7629204E-7).

BP6

Variant 9-120528758-C-G is Benign according to our data. Variant chr9-120528758-C-G is described in ClinVar as [Benign]. Clinvar id is 21657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120528758-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.922 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.865G>C	p.Glu289Gln	missense_variant	9/38	ENST00000349780.9	NP_060719.4	Q96SN8-1B3KVI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9 linkuse as main transcript	c.865G>C	p.Glu289Gln	missense_variant	9/38	1	NM_018249.6	ENSP00000343818.4		Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.843

AC:

128226

AN:

152030

Hom.:

55063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.954

Gnomad AMR

AF:

0.856

Gnomad ASJ

AF:

0.929

Gnomad EAS

AF:

0.711

Gnomad SAS

AF:

0.871

Gnomad FIN

AF:

0.923

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.928

Gnomad OTH

AF:

0.866

GnomAD3 exomes

AF:

0.879

AC:

220722

AN:

251222

Hom.:

97812

AF XY:

0.885

AC XY:

120105

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.674

Gnomad AMR exome

AF:

0.858

Gnomad ASJ exome

AF:

0.925

Gnomad EAS exome

AF:

0.721

Gnomad SAS exome

AF:

0.880

Gnomad FIN exome

AF:

0.929

Gnomad NFE exome

AF:

0.924

Gnomad OTH exome

AF:

0.903

GnomAD4 exome

AF:

0.912

AC:

1325495

AN:

1454122

Hom.:

606530

Cov.:

AF XY:

0.912

AC XY:

659984

AN XY:

723976

show subpopulations

Gnomad4 AFR exome

AF:

0.676

Gnomad4 AMR exome

AF:

0.856

Gnomad4 ASJ exome

AF:

0.930

Gnomad4 EAS exome

AF:

0.714

Gnomad4 SAS exome

AF:

0.881

Gnomad4 FIN exome

AF:

0.926

Gnomad4 NFE exome

AF:

0.930

Gnomad4 OTH exome

AF:

0.891

GnomAD4 genome

AF:

0.843

AC:

128284

AN:

152148

Hom.:

55080

Cov.:

AF XY:

0.843

AC XY:

62682

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.681

Gnomad4 AMR

AF:

0.856

Gnomad4 ASJ

AF:

0.929

Gnomad4 EAS

AF:

0.712

Gnomad4 SAS

AF:

0.871

Gnomad4 FIN

AF:

0.923

Gnomad4 NFE

AF:

0.928

Gnomad4 OTH

AF:

0.865

Alfa

AF:

0.909

Hom.:

47736

Bravo

AF:

0.831

TwinsUK

AF:

0.939

AC:

3480

ALSPAC

AF:

0.934

AC:

3600

ESP6500AA

AF:

0.693

AC:

3053

ESP6500EA

AF:

0.928

AC:

7981

ExAC

AF:

0.877

AC:

106466

Asia WGS

AF:

0.753

AC:

2619

AN:

3478

EpiCase

AF:

0.927

EpiControl

AF:

0.928

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	-	- -
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 provided, no classification provided	literature only	GeneReviews	-	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -

not provided

Benign:3

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

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

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T;.;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

T;T;T;T

MetaRNN

Benign

7.8e-7

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;L;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.61

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.15

T;T;T;T

Sift4G

Uncertain

0.0070

D;D;D;.

Polyphen

0.90, 0.0030

.;P;B;.

Vest4

0.23

MPC

0.18

ClinPred

0.026

GERP RS

4.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.13

gMVP

0.22

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