Variant 9-120389292-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018249.6(CDK5RAP2):c.5626C>G(p.Leu1876Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense, splice_region

Scores

Splicing: ADA: 0.001686

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.1596789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 linkuse as main transcript	c.5626C>G	p.Leu1876Val	missense_variant, splice_region_variant	38/38	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9 linkuse as main transcript	c.5626C>G	p.Leu1876Val	missense_variant, splice_region_variant	38/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459446

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725762

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2021

The c.5626C>G (p.L1876V) alteration is located in exon 38 (coding exon 38) of the CDK5RAP2 gene. This alteration results from a C to G substitution at nucleotide position 5626, causing the leucine (L) at amino acid position 1876 to be replaced by a valine (V). The p.L1876V alteration is predicted to be tolerated by in silico analysis. 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

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.071

.;T;.;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.;.;.

MutationTaster

Benign

0.91

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.71

.;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.42

.;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T

Polyphen

1.0, 0.99, 0.11, 0.050

.;D;D;B;B

Vest4

0.41

MutPred

0.14

.;Gain of MoRF binding (P = 0.0794);.;.;.;

MVP

0.32

MPC

0.39

ClinPred

0.44

GERP RS

5.3

Varity_R

0.062

gMVP

0.060

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0017

dbscSNV1_RF

Benign

0.10

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over