rs41296081

Positions:

chr9-120477365-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018249.6(CDK5RAP2):c.1712T>C(p.Leu571Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00792 in 1,610,960 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 71 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 5.14

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072303414).

BP6

Variant 9-120477365-A-G is Benign according to our data. Variant chr9-120477365-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 21642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00758 (1155/152356) while in subpopulation NFE AF= 0.0116 (789/68026). AF 95% confidence interval is 0.0109. There are 7 homozygotes in gnomad4. There are 593 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 linkuse as main transcript	c.1712T>C	p.Leu571Pro	missense_variant	15/38	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.1712T>C	p.Leu571Pro	missense_variant	15/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.00759

AC:

1155

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0201

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0116

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00844

AC:

2120

AN:

251252

Hom.:

AF XY:

0.00876

AC XY:

1190

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00796

AC:

11610

AN:

1458604

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

5883

AN XY:

725838

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.00540

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0220

Gnomad4 NFE exome

AF:

0.00867

Gnomad4 OTH exome

AF:

0.00758

GnomAD4 genome

AF:

0.00758

AC:

1155

AN:

152356

Hom.:

Cov.:

AF XY:

0.00796

AC XY:

593

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00635

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0201

Gnomad4 NFE

AF:

0.0116

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00620

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.00868

AC:

1054

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CDK5RAP2: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 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. -

Microcephaly 3, primary, autosomal recessive

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0010

D;D;D

Sift4G

Benign

0.070

T;D;D

Polyphen

1.0

.;D;D

Vest4

0.39

MVP

0.67

MPC

0.54

ClinPred

0.019

GERP RS

5.7

Varity_R

0.80

gMVP

0.63

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