9-120394512-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018249.6(CDK5RAP2):c.5578T>C(p.Leu1860Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,614,160 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 170 hom. )

Consequence

CDK5RAP2
NM_018249.6 splice_region, synonymous

Scores

Splicing: ADA: 0.0003015

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.809

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:

ENSG00000301087 (HGNC:):

ENSG00000301087 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 9-120394512-A-G is Benign according to our data. Variant chr9-120394512-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0802 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	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5RAP2	NM_018249.6	MANE Select	c.5578T>C	p.Leu1860Leu	splice_region synonymous	Exon 36 of 38	NP_060719.4
CDK5RAP2	NM_001410994.1		c.5575T>C	p.Leu1859Leu	splice_region synonymous	Exon 36 of 38	NP_001397923.1	A0A8I5QKL1
CDK5RAP2	NM_001410993.1		c.5482T>C	p.Leu1828Leu	splice_region synonymous	Exon 35 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.5578T>C	p.Leu1860Leu	splice_region synonymous	Exon 36 of 38	ENSP00000343818.4	Q96SN8-1
CDK5RAP2	ENST00000360190.8	TSL:1	c.5341T>C	p.Leu1781Leu	splice_region synonymous	Exon 35 of 37	ENSP00000353317.4	Q96SN8-4
CDK5RAP2	ENST00000473282.6	TSL:1	n.*4402T>C		splice_region non_coding_transcript_exon	Exon 37 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes

AF:

0.00344

AC:

523

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0867

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00748

AC:

1880

AN:

251478

AF XY:

0.00710

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00813

Gnomad EAS exome

AF:

0.0931

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00280

AC:

4089

AN:

1461854

Hom.:

170

Cov.:

AF XY:

0.00268

AC XY:

1952

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00796

AC:

208

AN:

26136

East Asian (EAS)

AF:

0.0851

AC:

3380

AN:

39700

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1112000

Other (OTH)

AF:

0.00512

AC:

309

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

232

463

695

926

1158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00343

AC:

523

AN:

152306

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

292

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41568

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.0869

AC:

449

AN:

5168

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68026

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00352

Hom.:

Bravo

AF:

0.00436

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

CDK5RAP2-related disorder (1)

Microcephaly 3, primary, autosomal recessive (1)

Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.2

(source)

DANN

Benign

0.65

PhyloP100

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=65/35

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.066

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: -4

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