rs10818456

Variant names:

• chr9-120447198-C-T
• rs10818456
• NM_018249.6:c.3025+697G>A

Variant summary

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

The NM_018249.6(CDK5RAP2):​c.3025+697G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 152,196 control chromosomes in the GnomAD database, including 339 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 0.055 (339 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 3 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0753 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	NM_018249.6	MANE Select	c.3025+697G>A		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.3022+697G>A		intron	N/A	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.2929+697G>A		intron	N/A	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.3025+697G>A		intron	N/A	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.3025+697G>A		intron	N/A	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*1849+697G>A		intron	N/A	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8363 AN: 152078 Hom.: 339 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0770

Gnomad OTH AF: 0.0492

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

GnomAD4 genome AF: 0.0549 AC: 8360 AN: 152196 Hom.: 339 Cov.: 32 AF XY: 0.0563 AC XY: 4188 AN XY: 74382

African (AFR) AF: 0.0140 AC: 580 AN: 41540

American (AMR) AF: 0.0296 AC: 453 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 218 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4820

European-Finnish (FIN) AF: 0.155 AC: 1640 AN: 10570

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0770 AC: 5238 AN: 68014

Other (OTH) AF: 0.0482 AC: 102 AN: 2114

Alfa AF: 0.0678 Hom.: 96

Bravo AF: 0.0453

Asia WGS AF: 0.00924 AC: 34 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	1.6
DANN	Benign	0.60
PhyloP100		0.27
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: rs10818456; hg19: chr9-123209476;