rs35909061

chr9-120408408-C-Achr9-120408408-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018249.6(CDK5RAP2):c.4665G>T(p.Gln1555His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,614,180 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.79

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=0.006692767).
• BP6: Variant 9-120408408-C-A is Benign according to our data. Variant chr9-120408408-C-A is described in ClinVar as [Benign]. Clinvar id is 21652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00366 (558/152332) while in subpopulation AFR AF= 0.0127 (529/41578). AF 95% confidence interval is 0.0118. There are 2 homozygotes in gnomad4. There are 286 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.4665G>T	p.Gln1555His	missense_variant	31/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.4665G>T	p.Gln1555His	missense_variant	31/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00110 AC: 277 AN: 251462 Hom.: 3 AF XY: 0.000758 AC XY: 103 AN XY: 135910

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000359 AC: 525 AN: 1461848 Hom.: 5 Cov.: 30 AF XY: 0.000285 AC XY: 207 AN XY: 727232

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00366 AC: 558 AN: 152332 Hom.: 2 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74500

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000512 Hom.: 0

Bravo AF: 0.00441

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 03, 2016

- -

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	0.26
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.036
Eigen_PC	Benign	0.055
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T;T;T;T;T
MetaRNN	Benign	0.0067	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Benign	0.34	T
REVEL	Benign	0.053
Sift4G	Benign	0.099	T;T;T;T;T
Polyphen		0.10, 1.0, 0.68, 0.63	.;B;D;P;P
Vest4		0.20
MutPred		0.12		.;Loss of ubiquitination at K1552 (P = 0.092);Loss of ubiquitination at K1552 (P = 0.092);.;.;
MVP		0.46
MPC		0.40
ClinPred		0.031	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.16

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: rs35909061; hg19: chr9-123170686;