9-120409306-C-A

Position:

chr9-120409306-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_018249.6(CDK5RAP2):c.4425G>T(p.Lys1475Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,593,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.75

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:

Genome browser will be placed here

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=0.20591015).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000153 (22/1441394) while in subpopulation AFR AF= 0.000424 (14/33010). AF 95% confidence interval is 0.000256. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome 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 linkuse as main transcript	c.4425G>T	p.Lys1475Asn	missense_variant	30/38	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.4425G>T	p.Lys1475Asn	missense_variant	30/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1441394

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

715446

show subpopulations

Gnomad4 AFR exome

AF:

0.000424

Gnomad4 AMR exome

AF:

0.0000486

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000838

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.4425G>T (p.K1475N) alteration is located in exon 30 (coding exon 30) of the CDK5RAP2 gene. This alteration results from a G to T substitution at nucleotide position 4425, causing the lysine (K) at amino acid position 1475 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Microcephaly 3, primary, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 27, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

CDK5RAP2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2024

The CDK5RAP2 c.4425G>T variant is predicted to result in the amino acid substitution p.Lys1475Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;T;.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Benign

0.060

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.0

.;M;M;.;.

MutationTaster

Benign

0.56

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.4

.;D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0010

.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.99, 1.0, 0.99

.;D;D;D;D

Vest4

0.54

MutPred

0.16

.;Loss of ubiquitination at K1475 (P = 0.0092);Loss of ubiquitination at K1475 (P = 0.0092);.;.;

MVP

0.29

MPC

0.44

ClinPred

0.84

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.20

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over