chr9-120400775-G-A

Variant names:

• chr9-120400775-G-A
• rs3739822
• NM_018249.6:c.5418C>T

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.5418C>T​(p.Pro1806Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,613,944 control chromosomes in the GnomAD database, including 658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (60 hom., cov: 32)
  • Exomes 𝑓: 0.026 (598 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.113
• Publications: 11 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

ENSG00000301087 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-120400775-G-A is Benign according to our data. Variant chr9-120400775-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.113 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0712 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.5418C>T	p.Pro1806Pro	synonymous	Exon 35 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.5415C>T	p.Pro1805Pro	synonymous	Exon 35 of 38	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.5322C>T	p.Pro1774Pro	synonymous	Exon 34 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.5418C>T	p.Pro1806Pro	synonymous	Exon 35 of 38	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.5181C>T	p.Pro1727Pro	synonymous	Exon 34 of 37	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*4242C>T		non_coding_transcript_exon	Exon 36 of 39	ENSP00000419265.1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3860 AN: 152114 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0239 AC: 6011 AN: 251370 AF XY: 0.0231

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.0411

Gnomad FIN exome AF: 0.0377

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0262 AC: 38362 AN: 1461712 Hom.: 598 Cov.: 31 AF XY: 0.0256 AC XY: 18589 AN XY: 727150

African (AFR) AF: 0.0218 AC: 729 AN: 33472

American (AMR) AF: 0.0128 AC: 571 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 451 AN: 26132

East Asian (EAS) AF: 0.0734 AC: 2913 AN: 39700

South Asian (SAS) AF: 0.00715 AC: 617 AN: 86248

European-Finnish (FIN) AF: 0.0351 AC: 1872 AN: 53408

Middle Eastern (MID) AF: 0.0399 AC: 226 AN: 5660

European-Non Finnish (NFE) AF: 0.0265 AC: 29416 AN: 1111996

Other (OTH) AF: 0.0260 AC: 1567 AN: 60372

GnomAD4 genome AF: 0.0254 AC: 3865 AN: 152232 Hom.: 60 Cov.: 32 AF XY: 0.0259 AC XY: 1926 AN XY: 74420

African (AFR) AF: 0.0224 AC: 932 AN: 41534

American (AMR) AF: 0.0156 AC: 239 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5174

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.0407 AC: 432 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1788 AN: 68012

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0246 Hom.: 88

Bravo AF: 0.0245

Asia WGS AF: 0.0410 AC: 141 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 08, 2015

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

PreventionGenetics, part of Exact Sciences

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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	-0.61
CADD	Benign	4.5
DANN	Benign	0.38
PhyloP100		-0.11
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: rs3739822; hg19: chr9-123163053;