rs2501727

Positions:

• chr9-120458551-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018249.6(CDK5RAP2):​c.2274T>C​(p.Asp758=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,613,736 control chromosomes in the GnomAD database, including 16,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3729 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12567 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.311

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-120458551-A-G is Benign according to our data. Variant chr9-120458551-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120458551-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.311 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.2274T>C	p.Asp758=	synonymous_variant	20/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.2274T>C	p.Asp758=	synonymous_variant	20/38	1	NM_018249.6	ENSP00000343818	P4

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28339 AN: 151978 Hom.: 3708 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0856

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0980

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.147 AC: 36956 AN: 251390 Hom.: 3635 AF XY: 0.141 AC XY: 19105 AN XY: 135864

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.0883

Gnomad EAS exome AF: 0.319

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.115 AC: 168786 AN: 1461640 Hom.: 12567 Cov.: 33 AF XY: 0.115 AC XY: 83606 AN XY: 727134

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.0837

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.0963

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.187 AC: 28408 AN: 152096 Hom.: 3729 Cov.: 32 AF XY: 0.188 AC XY: 13972 AN XY: 74370

Gnomad4 AFR AF: 0.355

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.0856

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0980

Gnomad4 OTH AF: 0.164

Alfa AF: 0.119 Hom.: 2396

Bravo AF: 0.198

Asia WGS AF: 0.292 AC: 1018 AN: 3478

EpiCase AF: 0.0983

EpiControl AF: 0.101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Dec 18, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Microcephaly 3, primary, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary Microcephaly, Recessive Benign:1

Likely 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
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.90
DANN	Benign	0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2501727; hg19: chr9-123220829; COSMIC: COSV62572597; COSMIC: COSV62572597;