9-120419924-C-T

Position:

• chr9-120419924-C-T

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.4041G>A​(p.Leu1347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,613,676 control chromosomes in the GnomAD database, including 2,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1149 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1569 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.26

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=-0.89).
• BP6: Variant 9-120419924-C-T is Benign according to our data. Variant chr9-120419924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120419924-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.4041G>A	p.Leu1347=	synonymous_variant	27/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.4041G>A	p.Leu1347=	synonymous_variant	27/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12903 AN: 152064 Hom.: 1141 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0400 AC: 10058 AN: 251472 Hom.: 561 AF XY: 0.0349 AC XY: 4740 AN XY: 135914

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.0391

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0331 AC: 48307 AN: 1461494 Hom.: 1569 Cov.: 31 AF XY: 0.0315 AC XY: 22884 AN XY: 727062

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0273

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0692

Gnomad4 SAS exome AF: 0.00764

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.0277

Gnomad4 OTH exome AF: 0.0423

GnomAD4 genome AF: 0.0851 AC: 12949 AN: 152182 Hom.: 1149 Cov.: 33 AF XY: 0.0840 AC XY: 6248 AN XY: 74398

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0419

Gnomad4 SAS AF: 0.00685

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0281

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0364 Hom.: 307

Bravo AF: 0.0930

Asia WGS AF: 0.0720 AC: 249 AN: 3478

EpiCase AF: 0.0272

EpiControl AF: 0.0299

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -

Primary Microcephaly, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6478475; hg19: chr9-123182202; COSMIC: COSV62576900;