Genetic Variant NM_018249.6:c.4727-192G>A (chr9-120407440-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018249.6(CDK5RAP2):c.4727-192G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 620,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CDK5RAP2
NM_018249.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.806

Publications

5 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:

ENSG00000301087 (HGNC:):

ENSG00000301087 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

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	UniProt
CDK5RAP2	NM_018249.6	MANE Select	c.4727-192G>A	intron	N/A	NP_060719.4
CDK5RAP2	NM_001410994.1		c.4724-192G>A	intron	N/A	NP_001397923.1	A0A8I5QKL1
CDK5RAP2	NM_001410993.1		c.4631-192G>A	intron	N/A	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.4727-192G>A	intron	N/A	ENSP00000343818.4	Q96SN8-1
CDK5RAP2	ENST00000360190.8	TSL:1	c.4726+907G>A	intron	N/A	ENSP00000353317.4	Q96SN8-4
CDK5RAP2	ENST00000483412.5	TSL:1	n.4941G>A	non_coding_transcript_exon	Exon 24 of 24

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

468408

Hom.:

Cov.:

AF XY:

0.00000806

AC XY:

AN XY:

247986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13118

American (AMR)

AF:

0.00

AC:

AN:

24042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15048

East Asian (EAS)

AF:

0.00

AC:

AN:

30982

South Asian (SAS)

AF:

0.00

AC:

AN:

48672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2266

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

277352

Other (OTH)

AF:

0.00

AC:

AN:

26852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2086

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

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:

0.00

Hom.:

2018

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.81

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