NM_018249.6:c.480A>C

Variant names:

• chr9-120539068-T-G
• rs3750494
• NM_018249.6:c.480A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 3, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• corpus callosum, agenesis of

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 136707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	NM_018249.6	MANE Select	c.480A>C	p.Leu160Leu	synonymous	Exon 6 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.480A>C	p.Leu160Leu	synonymous	Exon 6 of 38	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.480A>C	p.Leu160Leu	synonymous	Exon 6 of 37	NP_001397922.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.480A>C	p.Leu160Leu	synonymous	Exon 6 of 38	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.480A>C	p.Leu160Leu	synonymous	Exon 6 of 37	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.477A>C		non_coding_transcript_exon	Exon 6 of 39	ENSP00000419265.1

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

GnomAD2 exomes AF: 0.0999 AC: 25121 AN: 251412 AF XY: 0.0996

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 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

African (AFR) AF: 0.0355 AC: 1187 AN: 33474

American (AMR) AF: 0.125 AC: 5570 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 1800 AN: 26130

East Asian (EAS) AF: 0.289 AC: 11454 AN: 39690

South Asian (SAS) AF: 0.119 AC: 10279 AN: 86250

European-Finnish (FIN) AF: 0.0739 AC: 3949 AN: 53402

Middle Eastern (MID) AF: 0.0638 AC: 368 AN: 5768

European-Non Finnish (NFE) AF: 0.0688 AC: 76509 AN: 1111632

Other (OTH) AF: 0.0883 AC: 5332 AN: 60368

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

African (AFR) AF: 0.0407 AC: 1692 AN: 41556

American (AMR) AF: 0.111 AC: 1702 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3468

East Asian (EAS) AF: 0.290 AC: 1499 AN: 5176

South Asian (SAS) AF: 0.130 AC: 628 AN: 4828

European-Finnish (FIN) AF: 0.0761 AC: 807 AN: 10610

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0705 AC: 4793 AN: 68012

Other (OTH) AF: 0.0762 AC: 161 AN: 2114

Alfa AF: 0.0686 Hom.: 656

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

Apr 02, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary Microcephaly, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.049
DANN	Benign	0.34
PhyloP100		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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