rs549081765

Positions:

chr9-120453767-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The ENST00000349780.9(CDK5RAP2):c.2482A>G(p.Lys828Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. K828K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CDK5RAP2
ENST00000349780.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0920

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009703487).

BP6

Variant 9-120453767-T-C is Benign according to our data. Variant chr9-120453767-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432919.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000903 (132/1461880) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 75 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 linkuse as main transcript	c.2482A>G	p.Lys828Glu	missense_variant	21/38	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.2482A>G	p.Lys828Glu	missense_variant	21/38	1	NM_018249.6	ENSP00000343818	P4	Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251438

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000118

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 2023	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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 432919). This variant has not been reported in the literature in individuals affected with CDK5RAP2-related conditions. This variant is present in population databases (rs549081765, gnomAD 0.06%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 828 of the CDK5RAP2 protein (p.Lys828Glu). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with sporadic Hirschsprung disease in published literature (Villalba-Benito et al., 2017); This variant is associated with the following publications: (PMID: 28740121) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 04, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.23

DANN

Benign

0.44

DEOGEN2

Benign

0.12

T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.61

T;T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.18

T;T;T

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.0010

B;B;B

Vest4

0.087

MutPred

0.093

Loss of ubiquitination at K828 (P = 0.0081);Loss of ubiquitination at K828 (P = 0.0081);.;

MVP

0.12

MPC

0.24

ClinPred

0.014

GERP RS

-4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.076

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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