rs34523498

chr9-120443703-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018249.6(CDK5RAP2):c.3065G>A(p.Gly1022Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,614,004 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (80 hom., cov: 33)
  • Exomes 𝑓: 0.027 (624 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.567

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001809448).
• BP6: Variant 9-120443703-C-T is Benign according to our data. Variant chr9-120443703-C-T is described in ClinVar as [Benign]. Clinvar id is 21645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120443703-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.3065G>A	p.Gly1022Glu	missense_variant	23/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.3065G>A	p.Gly1022Glu	missense_variant	23/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4408 AN: 152136 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0408

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0250 AC: 6273 AN: 251176 Hom.: 112 AF XY: 0.0240 AC XY: 3260 AN XY: 135722

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0378

Gnomad SAS exome AF: 0.00683

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0273 AC: 39917 AN: 1461750 Hom.: 624 Cov.: 32 AF XY: 0.0266 AC XY: 19328 AN XY: 727176

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.0680

Gnomad4 SAS exome AF: 0.00710

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.0276

Gnomad4 OTH exome AF: 0.0268

GnomAD4 genome AF: 0.0290 AC: 4418 AN: 152254 Hom.: 80 Cov.: 33 AF XY: 0.0293 AC XY: 2184 AN XY: 74420

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.0409

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0273

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0283 Hom.: 121

Bravo AF: 0.0287

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.0290 AC: 249

ExAC AF: 0.0263 AC: 3191

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Microcephaly 3, primary, autosomal recessive Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.31	T
REVEL	Benign	0.027
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.053, 0.24, 1.0	.;B;B;D
Vest4		0.15
MPC		0.48
ClinPred		0.0062	T
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.086
gMVP		0.10

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: rs34523498; hg19: chr9-123205981; COSMIC: COSV62574106; COSMIC: COSV62574106;