9-120458551-A-G

Variant names:

• chr9-120458551-A-G
• rs2501727
• NM_018249.6:c.2274T>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.2274T>C​(p.Asp758Asp) 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
• Publications: 22 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=-0.92).
• BP6: Variant 9-120458551-A-G is Benign according to our data. Variant chr9-120458551-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2274T>C	p.Asp758Asp	synonymous	Exon 20 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.2271T>C	p.Asp757Asp	synonymous	Exon 20 of 38	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.2178T>C	p.Asp726Asp	synonymous	Exon 19 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.2274T>C	p.Asp758Asp	synonymous	Exon 20 of 38	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.2274T>C	p.Asp758Asp	synonymous	Exon 20 of 37	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*1098T>C		non_coding_transcript_exon	Exon 21 of 39	ENSP00000419265.1

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

GnomAD2 exomes AF: 0.147 AC: 36956 AN: 251390 AF XY: 0.141

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 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

African (AFR) AF: 0.359 AC: 12003 AN: 33470

American (AMR) AF: 0.155 AC: 6935 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0837 AC: 2187 AN: 26136

East Asian (EAS) AF: 0.353 AC: 14027 AN: 39692

South Asian (SAS) AF: 0.137 AC: 11788 AN: 86252

European-Finnish (FIN) AF: 0.109 AC: 5844 AN: 53420

Middle Eastern (MID) AF: 0.133 AC: 769 AN: 5768

European-Non Finnish (NFE) AF: 0.0963 AC: 107020 AN: 1111788

Other (OTH) AF: 0.136 AC: 8213 AN: 60390

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

African (AFR) AF: 0.355 AC: 14734 AN: 41486

American (AMR) AF: 0.164 AC: 2512 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 297 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1705 AN: 5164

South Asian (SAS) AF: 0.146 AC: 704 AN: 4824

European-Finnish (FIN) AF: 0.118 AC: 1248 AN: 10572

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0980 AC: 6665 AN: 67980

Other (OTH) AF: 0.164 AC: 345 AN: 2108

Alfa AF: 0.125 Hom.: 3321

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

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 18, 2013

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

Microcephaly 3, primary, autosomal recessive Benign:2

Jun 28, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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	-0.92
CADD	Benign	0.90
DANN	Benign	0.27
PhyloP100		-0.31
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)		0.040		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: rs2501727; hg19: chr9-123220829; COSMIC: COSV62572597; COSMIC: COSV62572597;