chr9-120539139-C-A

Variant names:

• chr9-120539139-C-A
• rs41302645
• NM_018249.6:c.409G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018249.6(CDK5RAP2):​c.409G>T​(p.Ala137Ser) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A137V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.74
• Publications: 1 publications found

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]

CDK5RAP2 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 3, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• corpus callosum, agenesis of

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058279604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.409G>T	p.Ala137Ser	missense_variant	Exon 6 of 38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.409G>T	p.Ala137Ser	missense_variant	Exon 6 of 38	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Microcephaly 3, primary, autosomal recessive Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	.;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	.;N;N
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.23	N;N;N
REVEL	Benign	0.024
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0050, 0.042	.;B;B
Vest4		0.063
MutPred		0.087		Gain of phosphorylation at A137 (P = 0.0188);Gain of phosphorylation at A137 (P = 0.0188);Gain of phosphorylation at A137 (P = 0.0188);
MVP		0.32
MPC		0.16
ClinPred		0.086	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.064
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs41302645; hg19: chr9-123301417;