rs587783385

Positions:

• chr9-120439836-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000349780.9(CDK5RAP2):​c.3285G>C​(p.Met1095Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK5RAP2 ENST00000349780.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.531

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027455747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.3285G>C	p.Met1095Ile	missense_variant	24/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.3285G>C	p.Met1095Ile	missense_variant	24/38	1	NM_018249.6	ENSP00000343818	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 3, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.41
DANN	Benign	0.28
DEOGEN2	Benign	0.095	.;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T;T;T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.90	.;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.57	.;N;N;N;N
REVEL	Benign	0.095
Sift	Benign	0.91	.;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;B;B
Vest4		0.056
MutPred		0.096		.;Gain of phosphorylation at T1097 (P = 0.0952);Gain of phosphorylation at T1097 (P = 0.0952);.;.;
MVP		0.072
MPC		0.083
ClinPred		0.026	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.043

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: rs587783385; hg19: chr9-123202114;