9-120539068-T-G

Position:

• chr9-120539068-T-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.480A>C​(p.Leu160Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,613,706 control chromosomes in the GnomAD database, including 6,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (685 hom., cov: 32)
  • Exomes 𝑓: 0.080 (6024 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.55

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-120539068-T-G is Benign according to our data. Variant chr9-120539068-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 136707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120539068-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.480A>C	p.Leu160Leu	synonymous_variant	6/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.480A>C	p.Leu160Leu	synonymous_variant	6/38	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11589 AN: 152154 Hom.: 686 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0761

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.0770

GnomAD3 exomes AF: 0.0999 AC: 25121 AN: 251412 Hom.: 1776 AF XY: 0.0996 AC XY: 13535 AN XY: 135872

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.0739

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0712

Gnomad NFE exome AF: 0.0741

Gnomad OTH exome AF: 0.0843

GnomAD4 exome AF: 0.0797 AC: 116448 AN: 1461434 Hom.: 6024 Cov.: 32 AF XY: 0.0808 AC XY: 58736 AN XY: 727032

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.0689

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0739

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0883

GnomAD4 genome AF: 0.0761 AC: 11583 AN: 152272 Hom.: 685 Cov.: 32 AF XY: 0.0793 AC XY: 5908 AN XY: 74464

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0761

Gnomad4 NFE AF: 0.0705

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.0681 Hom.: 537

Bravo AF: 0.0767

Asia WGS AF: 0.208 AC: 724 AN: 3476

EpiCase AF: 0.0707

EpiControl AF: 0.0704

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	-0.90
CADD	Benign	0.049
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3750494; hg19: chr9-123301346; COSMIC: COSV62572603; COSMIC: COSV62572603;