chr9-120530054-G-A

Position:

chr9-120530054-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018249.6(CDK5RAP2):c.749C>T(p.Pro250Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,613,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.579

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057652593).

BP6

Variant 9-120530054-G-A is Benign according to our data. Variant chr9-120530054-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158170.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152276) while in subpopulation SAS AF= 0.00393 (19/4830). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 linkuse as main transcript	c.749C>T	p.Pro250Leu	missense_variant	8/38	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.749C>T	p.Pro250Leu	missense_variant	8/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000482

AC:

121

AN:

251252

Hom.:

AF XY:

0.000619

AC XY:

AN XY:

135790

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:

0.00385

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000244

AC:

356

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

727146

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:

0.00392

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000131

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000264

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly 3, primary, autosomal recessive

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2014	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;.;T

Eigen

Benign

-0.022

Eigen_PC

Benign

0.092

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

T;T;T;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.1

.;L;L;.

MutationTaster

Benign

0.92

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Benign

0.055

Sift

Benign

0.35

T;T;T;D

Sift4G

Benign

0.063

T;D;T;.

Polyphen

0.27, 0.036

.;B;B;.

Vest4

0.26

MutPred

0.18

Gain of catalytic residue at P250 (P = 0.0551);Gain of catalytic residue at P250 (P = 0.0551);Gain of catalytic residue at P250 (P = 0.0551);.;

MVP

0.69

MPC

0.31

ClinPred

0.11

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.13

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