Genetic Variant CDK5R2:p.Pro174Leu (chr2-218960341-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003936.5(CDK5R2):c.521C>T(p.Pro174Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000398 in 1,508,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

CDK5R2
NM_003936.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89

Publications

0 publications found

Variant links:

Genes affected

CDK5R2 (HGNC:1776): (cyclin dependent kinase 5 regulatory subunit 2) The protein encoded by this gene is a neuron-specific activator of CDK5 kinase. It associates with CDK5 to form an active kinase. This protein and neuron-specific CDK5 activator CDK5R1/p39NCK5A both share limited similarity to cyclins, and thus may define a distinct family of cyclin-dependent kinase activating proteins. [provided by RefSeq, Jul 2008]

CDK5R2 links:

CDK5R2-AS1 (HGNC:55677): (CDK5R2 antisense RNA 1)

CDK5R2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003936.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5R2	NM_003936.5	MANE Select	c.521C>T	p.Pro174Leu	missense	Exon 1 of 1	NP_003927.1	Q13319

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5R2	ENST00000302625.6	TSL:6 MANE Select	c.521C>T	p.Pro174Leu	missense	Exon 1 of 1	ENSP00000304250.4	Q13319
CDK5R2-AS1	ENST00000429343.1	TSL:4	n.45+1518G>A		intron	N/A
CDK5R2-AS1	ENST00000798770.1		n.277+1518G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151674

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000188

AC:

AN:

106614

AF XY:

0.0000167

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000496

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1356814

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

669510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28006

American (AMR)

AF:

0.00

AC:

AN:

32316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24168

East Asian (EAS)

AF:

0.00

AC:

AN:

31698

South Asian (SAS)

AF:

0.00

AC:

AN:

76828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4954

European-Non Finnish (NFE)

AF:

0.00000375

AC:

AN:

1067186

Other (OTH)

AF:

0.0000177

AC:

AN:

56584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151674

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67834

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.1

PhyloP100

6.9

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.43

MutPred

0.73

Loss of glycosylation at P174 (P = 0.019)

MVP

0.92

ClinPred

0.94

GERP RS

3.8

Varity_R

0.63

gMVP

0.74

Mutation Taster

=57/43

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over