chr9-120463648-T-C

Variant names:

• chr9-120463648-T-C
• rs7869290
• NM_018249.6:c.2107-2981A>G

Variant summary

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

The NM_018249.6(CDK5RAP2):​c.2107-2981A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 152,094 control chromosomes in the GnomAD database, including 8,485 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 0.33 (8485 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.366 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.2107-2981A>G		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.2104-2981A>G		intron	N/A	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.2106+4212A>G		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.2107-2981A>G		intron	N/A	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.2107-2981A>G		intron	N/A	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*851-2901A>G		intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49654 AN: 151976 Hom.: 8477 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.338

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

GnomAD4 genome AF: 0.327 AC: 49697 AN: 152094 Hom.: 8485 Cov.: 32 AF XY: 0.321 AC XY: 23852 AN XY: 74358

African (AFR) AF: 0.320 AC: 13279 AN: 41476

American (AMR) AF: 0.270 AC: 4133 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1241 AN: 3472

East Asian (EAS) AF: 0.135 AC: 697 AN: 5154

South Asian (SAS) AF: 0.132 AC: 637 AN: 4824

European-Finnish (FIN) AF: 0.322 AC: 3408 AN: 10574

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25119 AN: 67984

Other (OTH) AF: 0.340 AC: 718 AN: 2112

Alfa AF: 0.343 Hom.: 17481

Bravo AF: 0.324

Asia WGS AF: 0.194 AC: 673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.66
DANN	Benign	0.29
PhyloP100		-0.45
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: rs7869290; hg19: chr9-123225926; COSMIC: COSV62573097;