rs36001459

chr9-120458536-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_018249.6(CDK5RAP2):c.2289C>T(p.His763=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,614,088 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (5 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.143

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-120458536-G-A is Benign according to our data. Variant chr9-120458536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120458536-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.143 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000637 (97/152302) while in subpopulation SAS AF= 0.00145 (7/4826). AF 95% confidence interval is 0.000848. There are 1 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.2289C>T	p.His763=	synonymous_variant	20/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.2289C>T	p.His763=	synonymous_variant	20/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00107 AC: 269 AN: 251400 Hom.: 1 AF XY: 0.00113 AC XY: 153 AN XY: 135872

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000882 AC: 1290 AN: 1461786 Hom.: 5 Cov.: 31 AF XY: 0.000914 AC XY: 665 AN XY: 727196

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.000997

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74482

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000671 Hom.: 0

Bravo AF: 0.000533

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CDK5RAP2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

CDK5RAP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.1
Dann	Benign	0.42
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs36001459; hg19: chr9-123220814; COSMIC: COSV100575156; COSMIC: COSV100575156;