9-120389279-C-T

Variant summary

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

The NM_018249.6(CDK5RAP2):​c.5639G>A​(p.Gly1880Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0930
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]

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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=0.1071794).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDK5RAP2NM_018249.6 linkc.5639G>A p.Gly1880Glu missense_variant Exon 38 of 38 ENST00000349780.9 NP_060719.4 Q96SN8-1B3KVI2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDK5RAP2ENST00000349780.9 linkc.5639G>A p.Gly1880Glu missense_variant Exon 38 of 38 1 NM_018249.6 ENSP00000343818.4 Q96SN8-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248110
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134026
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000891
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460060
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726180
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1880 of the CDK5RAP2 protein (p.Gly1880Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDK5RAP2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
8.8
DANN
Benign
0.96
DEOGEN2
Benign
0.10
.;T;.;.;.
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.024
N
LIST_S2
Uncertain
0.87
D;D;D;D;D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.11
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
.;L;.;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.9
.;N;N;N;D
REVEL
Benign
0.057
Sift
Benign
0.052
.;T;D;T;T
Sift4G
Uncertain
0.015
D;D;D;D;D
Polyphen
0.062, 0.90, 0.87, 0.76
.;B;P;P;P
Vest4
0.25
MutPred
0.16
.;Loss of catalytic residue at G1880 (P = 0.0322);.;.;.;
MVP
0.28
MPC
0.49
ClinPred
0.45
T
GERP RS
-3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.039
gMVP
0.040

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1179812147; hg19: chr9-123151557; API