rs10125592

Variant names:

• chr9-120399457-A-G
• rs10125592
• NM_018249.6:c.5451+1285T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-120399457-A-G
• chr9-120399457-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018249.6(CDK5RAP2):​c.5451+1285T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,164 control chromosomes in the GnomAD database, including 3,711 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 0.21 (3711 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 20 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

ENSG00000301087 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	NM_018249.6	MANE Select	c.5451+1285T>C		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.5448+1285T>C		intron	N/A	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.5355+1285T>C		intron	N/A	NP_001397922.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.5451+1285T>C		intron	N/A	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.5214+1285T>C		intron	N/A	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*4275+1285T>C		intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31766 AN: 152046 Hom.: 3705 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.209 AC: 31807 AN: 152164 Hom.: 3711 Cov.: 32 AF XY: 0.208 AC XY: 15494 AN XY: 74392

African (AFR) AF: 0.302 AC: 12542 AN: 41480

American (AMR) AF: 0.211 AC: 3230 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1411 AN: 5168

South Asian (SAS) AF: 0.154 AC: 743 AN: 4824

European-Finnish (FIN) AF: 0.156 AC: 1653 AN: 10604

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11068 AN: 68000

Other (OTH) AF: 0.202 AC: 426 AN: 2110

Alfa AF: 0.176 Hom.: 7586

Bravo AF: 0.217

Asia WGS AF: 0.249 AC: 867 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-0.14
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: rs10125592; hg19: chr9-123161735; COSMIC: COSV62573053;