9-120467963-T-A

Variant names:

• chr9-120467963-T-A
• rs137966123
• NM_018249.6:c.2003A>T

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.2003A>T​(p.Tyr668Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y668C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• Publications: 6 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• corpus callosum, agenesis of

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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=0.22189847).

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.2003A>T	p.Tyr668Phe	missense	Exon 18 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.2000A>T	p.Tyr667Phe	missense	Exon 18 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.2003A>T	p.Tyr668Phe	missense	Exon 18 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.2003A>T	p.Tyr668Phe	missense	Exon 18 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.2003A>T	p.Tyr668Phe	missense	Exon 18 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*747A>T		non_coding_transcript_exon	Exon 19 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.068
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.48	T
Polyphen		0.85	P
Vest4		0.30
MutPred		0.20		Gain of methylation at K665 (P = 0.103)
MVP		0.49
MPC		0.37
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.090
gMVP		0.092
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: rs137966123; hg19: chr9-123230241;