9-120389271-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018249.6(CDK5RAP2):c.5647C>T(p.Pro1883Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1883P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13588792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.5647C>T	p.Pro1883Ser	missense_variant	38/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.5647C>T	p.Pro1883Ser	missense_variant	38/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000402 AC: 10 AN: 248984 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460662 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.5647C>T (p.P1883S) alteration is located in exon 38 (coding exon 38) of the CDK5RAP2 gene. This alteration results from a C to T substitution at nucleotide position 5647, causing the proline (P) at amino acid position 1883 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.015
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Benign	0.036
Sift	Benign	0.071	T;T;T;T;T
Sift4G	Benign	0.072	T;T;T;T;T
Polyphen		0.20, 1.0, 0.84, 0.96	.;B;D;P;D
Vest4		0.20
MutPred		0.21		.;Gain of glycosylation at P1883 (P = 0.026);.;.;.;
MVP		0.55
MPC		0.42
ClinPred		0.53	D
GERP RS		3.3
Varity_R		0.051
gMVP		0.088

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: rs1211671769; hg19: chr9-123151549;