9-120443634-C-G

Position:

chr9-120443634-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.3134G>C(p.Arg1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,972 control chromosomes in the GnomAD database, including 2,029 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 773 hom., cov: 33)

Exomes 𝑓: 0.032 ( 1256 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.31

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=0.0011312366).

BP6

Variant 9-120443634-C-G is Benign according to our data. Variant chr9-120443634-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 21646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120443634-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 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.3134G>C	p.Arg1045Thr	missense_variant	23/38	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.3134G>C	p.Arg1045Thr	missense_variant	23/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11100

AN:

152124

Hom.:

767

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0376

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0410

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.0413

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0279

Gnomad OTH

AF:

0.0535

GnomAD3 exomes

AF:

0.0369

AC:

9282

AN:

251322

Hom.:

422

AF XY:

0.0326

AC XY:

4434

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0383

Gnomad SAS exome

AF:

0.00728

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0286

Gnomad OTH exome

AF:

0.0356

GnomAD4 exome

AF:

0.0320

AC:

46716

AN:

1461730

Hom.:

1256

Cov.:

AF XY:

0.0306

AC XY:

22217

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.186

Gnomad4 AMR exome

AF:

0.0249

Gnomad4 ASJ exome

AF:

0.0150

Gnomad4 EAS exome

AF:

0.0685

Gnomad4 SAS exome

AF:

0.00750

Gnomad4 FIN exome

AF:

0.0359

Gnomad4 NFE exome

AF:

0.0280

Gnomad4 OTH exome

AF:

0.0388

GnomAD4 genome

AF:

0.0731

AC:

11135

AN:

152242

Hom.:

773

Cov.:

AF XY:

0.0727

AC XY:

5409

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.185

Gnomad4 AMR

AF:

0.0375

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.0411

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0413

Gnomad4 NFE

AF:

0.0279

Gnomad4 OTH

AF:

0.0581

Alfa

AF:

0.0310

Hom.:

145

Bravo

AF:

0.0797

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.182

AC:

801

ESP6500EA

AF:

0.0297

AC:

255

ExAC

AF:

0.0408

AC:

4948

Asia WGS

AF:

0.0670

AC:

231

AN:

3478

EpiCase

AF:

0.0270

EpiControl

AF:

0.0301

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary Microcephaly, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Microcephaly 3, primary, autosomal recessive

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.046

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.12

T;T;T;T

MetaRNN

Benign

0.0011

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.4

.;N;N;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

0.69

.;N;N;N

REVEL

Benign

0.070

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;B

Vest4

0.067

MPC

0.11

ClinPred

0.0033

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.069

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