chr9-120400775-G-A

Position:

• chr9-120400775-G-A

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.5418C>T​(p.Pro1806=) 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

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=-0.61).
• BP6: Variant 9-120400775-G-A is Benign according to our data. Variant chr9-120400775-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120400775-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.5418C>T	p.Pro1806=	synonymous_variant	35/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.5418C>T	p.Pro1806=	synonymous_variant	35/38	1	NM_018249.6	ENSP00000343818	P4

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

GnomAD3 exomes AF: 0.0239 AC: 6011 AN: 251370 Hom.: 109 AF XY: 0.0231 AC XY: 3138 AN XY: 135846

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 SAS exome AF: 0.00699

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

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.0734

Gnomad4 SAS exome AF: 0.00715

Gnomad4 FIN exome AF: 0.0351

Gnomad4 NFE exome AF: 0.0265

Gnomad4 OTH exome AF: 0.0260

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

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0417

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0407

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0250 Hom.: 73

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2015	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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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