9-120408455-C-T

Position:

• chr9-120408455-C-T

Variant summary

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

The NM_018249.6(CDK5RAP2):​c.4618G>A​(p.Val1540Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V1540L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720

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=0.03129232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.4618G>A	p.Val1540Met	missense_variant	31/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.4618G>A	p.Val1540Met	missense_variant	31/38	1	NM_018249.6	ENSP00000343818	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 47 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.55
DEOGEN2	Benign	0.093	.;T;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	.;N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.89	.;N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.60	.;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T
Polyphen		0.068, 0.026, 0.64, 0.40	.;B;B;P;B
Vest4		0.14
MutPred		0.11		.;Gain of catalytic residue at V1536 (P = 0.0301);Gain of catalytic residue at V1536 (P = 0.0301);.;.;
MVP		0.17
MPC		0.36
ClinPred		0.15	T
GERP RS		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.018
gMVP		0.084

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: rs4837768; hg19: chr9-123170733;