Genetic Variant CDK5RAP2:p.Thr308Ile (chr9-120527882-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018249.6(CDK5RAP2):c.923C>T(p.Thr308Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,613,628 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 2 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.36

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
microcephaly 3, primary, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
corpus callosum, agenesis of
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CDK5RAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03480223).

BP6

Variant 9-120527882-G-A is Benign according to our data. Variant chr9-120527882-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158173.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000263 (40/152186) while in subpopulation SAS AF = 0.00083 (4/4818). AF 95% confidence interval is 0.000283. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5RAP2	NM_018249.6	MANE Select	c.923C>T	p.Thr308Ile	missense	Exon 10 of 38	NP_060719.4
CDK5RAP2	NM_001410994.1		c.923C>T	p.Thr308Ile	missense	Exon 10 of 38	NP_001397923.1	A0A8I5QKL1
CDK5RAP2	NM_001410993.1		c.923C>T	p.Thr308Ile	missense	Exon 10 of 37	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.923C>T	p.Thr308Ile	missense	Exon 10 of 38	ENSP00000343818.4	Q96SN8-1
CDK5RAP2	ENST00000360190.8	TSL:1	c.923C>T	p.Thr308Ile	missense	Exon 10 of 37	ENSP00000353317.4	Q96SN8-4
CDK5RAP2	ENST00000473282.6	TSL:1	n.920C>T		non_coding_transcript_exon	Exon 10 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000489

AC:

123

AN:

251286

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000501

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000359

AC:

525

AN:

1461442

Hom.:

Cov.:

AF XY:

0.000410

AC XY:

298

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000246

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00210

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00103

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000273

AC:

303

AN:

1111784

Other (OTH)

AF:

0.000845

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41522

American (AMR)

AF:

0.000327

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000830

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000592

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Microcephaly 3, primary, autosomal recessive (2)

CDK5RAP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.79

M_CAP

Benign

0.010

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

PhyloP100

1.4

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.5

REVEL

Benign

0.087

Sift

Uncertain

0.011

Sift4G

Benign

0.18

Polyphen

0.67

Vest4

0.18

MVP

0.47

MPC

0.23

ClinPred

0.16

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.057

gMVP

0.16

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over