rs75029577

Variant names:

• chr9-120518659-C-T
• rs75029577
• NM_018249.6:c.1093-14G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018249.6(CDK5RAP2):​c.1093-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,608,532 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (57 hom., cov: 29)
  • Exomes 𝑓: 0.028 (676 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0770
• Publications: 1 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-120518659-C-T is Benign according to our data. Variant chr9-120518659-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3245/151878) while in subpopulation NFE AF = 0.0291 (1975/67946). AF 95% confidence interval is 0.028. There are 57 homozygotes in GnomAd4. There are 1686 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.1093-14G>A		intron_variant	Intron 11 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.1093-14G>A		intron_variant	Intron 11 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3243 AN: 151760 Hom.: 57 Cov.: 29

Gnomad AFR AF: 0.00506

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0238 AC: 5972 AN: 251054 AF XY: 0.0246

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.00760

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0284 AC: 41338 AN: 1456654 Hom.: 676 Cov.: 29 AF XY: 0.0286 AC XY: 20733 AN XY: 725094

African (AFR) AF: 0.00374 AC: 125 AN: 33390

American (AMR) AF: 0.00749 AC: 335 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 211 AN: 26108

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39676

South Asian (SAS) AF: 0.0288 AC: 2481 AN: 86070

European-Finnish (FIN) AF: 0.0557 AC: 2976 AN: 53382

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5756

European-Non Finnish (NFE) AF: 0.0304 AC: 33642 AN: 1107332

Other (OTH) AF: 0.0246 AC: 1482 AN: 60220

GnomAD4 genome AF: 0.0214 AC: 3245 AN: 151878 Hom.: 57 Cov.: 29 AF XY: 0.0227 AC XY: 1686 AN XY: 74230

African (AFR) AF: 0.00505 AC: 209 AN: 41422

American (AMR) AF: 0.0121 AC: 184 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0263 AC: 125 AN: 4752

European-Finnish (FIN) AF: 0.0606 AC: 640 AN: 10564

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1975 AN: 67946

Other (OTH) AF: 0.0143 AC: 30 AN: 2102

Alfa AF: 0.0235 Hom.: 10

Bravo AF: 0.0167

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 18, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary Microcephaly, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.70
PhyloP100		0.077
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75029577; hg19: chr9-123280937;