rs145165171

chr9-120524999-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018249.6(CDK5RAP2):c.1079C>T(p.Thr360Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,613,648 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T360T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.64

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036424696).
• BP6: Variant 9-120524999-G-A is Benign according to our data. Variant chr9-120524999-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158126.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000755 (115/152298) while in subpopulation NFE AF= 0.00141 (96/68026). AF 95% confidence interval is 0.00118. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.1079C>T	p.Thr360Ile	missense_variant	11/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.1079C>T	p.Thr360Ile	missense_variant	11/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000760 AC: 191 AN: 251348 Hom.: 0 AF XY: 0.000707 AC XY: 96 AN XY: 135828

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00101 AC: 1477 AN: 1461350 Hom.: 3 Cov.: 30 AF XY: 0.000979 AC XY: 712 AN XY: 727006

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74464

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000744

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000939 AC: 114

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 24, 2012	- -

Microcephaly 3, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2022

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 360 of the CDK5RAP2 protein (p.Thr360Ile). This variant is present in population databases (rs145165171, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CDK5RAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 158126). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	-0.57	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	2.9
Dann	Uncertain	0.98
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.20	N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.54	T;T;T;T
Sift4G	Benign	0.75	T;T;T;.
Polyphen		0.0	.;B;B;.
Vest4		0.045
MVP		0.40
MPC		0.081
ClinPred		0.0031	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
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: rs145165171; hg19: chr9-123287277;