Genetic Variant NM_018249.6:c.128-1605T>A (chr9-120569993-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018249.6(CDK5RAP2):c.128-1605T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,082 control chromosomes in the GnomAD database, including 2,393 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2393 hom., cov: 32)

Consequence

CDK5RAP2
NM_018249.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.239

Publications

2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
corpus callosum, agenesis of
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CDK5RAP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

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	Effect	Exon Rank	Protein
CDK5RAP2	NM_018249.6	MANE Select	c.128-1605T>A	intron	N/A	NP_060719.4
CDK5RAP2	NM_001410994.1		c.128-1605T>A	intron	N/A	NP_001397923.1
CDK5RAP2	NM_001410993.1		c.128-1605T>A	intron	N/A	NP_001397922.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.128-1605T>A	intron	N/A	ENSP00000343818.4
CDK5RAP2	ENST00000360190.8	TSL:1	c.128-1605T>A	intron	N/A	ENSP00000353317.4
CDK5RAP2	ENST00000473282.6	TSL:1	n.125-1605T>A	intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26371

AN:

151964

Hom.:

2394

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.399

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.0846

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.197

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.173

AC:

26369

AN:

152082

Hom.:

2393

Cov.:

AF XY:

0.173

AC XY:

12830

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.124

AC:

5123

AN:

41478

American (AMR)

AF:

0.200

AC:

3052

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

709

AN:

3468

East Asian (EAS)

AF:

0.0846

AC:

438

AN:

5180

South Asian (SAS)

AF:

0.196

AC:

944

AN:

4820

European-Finnish (FIN)

AF:

0.151

AC:

1593

AN:

10576

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13653

AN:

67972

Other (OTH)

AF:

0.197

AC:

416

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1092

2184

3275

4367

5459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.184

Hom.:

329

Bravo

AF:

0.175

Asia WGS

AF:

0.147

AC:

511

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.9

(source)

DANN

Benign

0.78

PhyloP100

0.24

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over