rs185208659
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_018249.6(CDK5RAP2):c.3769C>T(p.Arg1257Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,614,094 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 1 hom. )
Consequence
CDK5RAP2
NM_018249.6 missense
NM_018249.6 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 1.60
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 Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12835795).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000854 (13/152288) while in subpopulation EAS AF= 0.00135 (7/5182). AF 95% confidence interval is 0.000633. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDK5RAP2 | NM_018249.6 | c.3769C>T | p.Arg1257Trp | missense_variant | 25/38 | ENST00000349780.9 | NP_060719.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDK5RAP2 | ENST00000349780.9 | c.3769C>T | p.Arg1257Trp | missense_variant | 25/38 | 1 | NM_018249.6 | ENSP00000343818.4 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251336Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135830
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GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461806Hom.: 1 Cov.: 32 AF XY: 0.0000591 AC XY: 43AN XY: 727216
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GnomAD4 genome AF: 0.0000854 AC: 13AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74462
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 29, 2015 | - - |
Microcephaly 3, primary, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 30, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 25, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 434655). This variant has not been reported in the literature in individuals affected with CDK5RAP2-related conditions. This variant is present in population databases (rs185208659, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1257 of the CDK5RAP2 protein (p.Arg1257Trp). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
.;M;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D;D;D
REVEL
Benign
Sift
Uncertain
.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
1.0, 1.0, 1.0, 0.99
.;D;D;D;D
Vest4
MVP
MPC
0.38
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at