chr9-120407932-G-C

Variant names:

• chr9-120407932-G-C
• rs914593
• NM_018249.6:c.4726+415C>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.4726+415C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 289,208 control chromosomes in the GnomAD database, including 92,259 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 0.80 (49095 hom., cov: 32)
  • Exomes 𝑓: 0.79 (43164 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.981
• 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

ENSG00000301087 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.854 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.4726+415C>G		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.4723+415C>G		intron	N/A	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.4630+415C>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.4726+415C>G		intron	N/A	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.4726+415C>G		intron	N/A	ENSP00000353317.4
	CDK5RAP2	ENST00000483412.5	TSL:1	n.4449C>G		non_coding_transcript_exon	Exon 24 of 24

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121972 AN: 152082 Hom.: 49066 Cov.: 32

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.799

GnomAD4 exome AF: 0.792 AC: 108480 AN: 137008 Hom.: 43164 Cov.: 0 AF XY: 0.795 AC XY: 57877 AN XY: 72758

African (AFR) AF: 0.801 AC: 3625 AN: 4524

American (AMR) AF: 0.877 AC: 5583 AN: 6368

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2456 AN: 3308

East Asian (EAS) AF: 0.870 AC: 5721 AN: 6578

South Asian (SAS) AF: 0.820 AC: 19757 AN: 24088

European-Finnish (FIN) AF: 0.836 AC: 5547 AN: 6638

Middle Eastern (MID) AF: 0.772 AC: 392 AN: 508

European-Non Finnish (NFE) AF: 0.767 AC: 59840 AN: 77980

Other (OTH) AF: 0.792 AC: 5559 AN: 7016

GnomAD4 genome AF: 0.802 AC: 122057 AN: 152200 Hom.: 49095 Cov.: 32 AF XY: 0.806 AC XY: 59999 AN XY: 74410

African (AFR) AF: 0.804 AC: 33360 AN: 41508

American (AMR) AF: 0.847 AC: 12952 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2615 AN: 3470

East Asian (EAS) AF: 0.875 AC: 4534 AN: 5180

South Asian (SAS) AF: 0.828 AC: 3996 AN: 4824

European-Finnish (FIN) AF: 0.860 AC: 9119 AN: 10608

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.776 AC: 52771 AN: 67998

Other (OTH) AF: 0.799 AC: 1687 AN: 2112

Alfa AF: 0.700 Hom.: 2014

Bravo AF: 0.805

Asia WGS AF: 0.867 AC: 3015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.052
DANN	Benign	0.45
PhyloP100		-0.98
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: rs914593; hg19: chr9-123170210;