NM_018249.6:c.4336A>C

Variant names:

• chr9-120411436-T-G
• NM_018249.6:c.4336A>C
• CDK5RAP2 p.Ser1446Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018249.6(CDK5RAP2):​c.4336A>C​(p.Ser1446Arg) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• corpus callosum, agenesis of

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000301087 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15739453).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	NM_018249.6	MANE Select	c.4336A>C	p.Ser1446Arg	missense	Exon 29 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.4333A>C	p.Ser1445Arg	missense	Exon 29 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.4240A>C	p.Ser1414Arg	missense	Exon 28 of 37	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.4336A>C	p.Ser1446Arg	missense	Exon 29 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.4336A>C	p.Ser1446Arg	missense	Exon 29 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*3160A>C		non_coding_transcript_exon	Exon 30 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.048
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.051
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-123173714;