rs4836822

chr9-120528758-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.64

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]

ACMG classification

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	UniProt
CDK5RAP2	NM_018249.6	c.865G>C	p.Glu289Gln	missense_variant	9/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.865G>C	p.Glu289Gln	missense_variant	9/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128226 AN: 152030 Hom.: 55063 Cov.: 32

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

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.: 33 AF XY: 0.912 AC XY: 659984 AN XY: 723976

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.: 32 AF XY: 0.843 AC XY: 62682 AN XY: 74368

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:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 3, primary, autosomal recessive Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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 specified Benign:3

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T;T;T;T
MetaRNN	Benign	7.8e-7	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.0045	P;P;P;P
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs4836822; hg19: chr9-123291036; COSMIC: COSV62573846;