chr9-120407889-G-A

Variant names:

• chr9-120407889-G-A
• rs914592
• ENST00000483412.5:n.4492C>T

Variant summary

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

The ENST00000483412.5(CDK5RAP2):​n.4492C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 254,970 control chromosomes in the GnomAD database, including 82,515 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 0.81 (50031 hom., cov: 31)
  • Exomes 𝑓: 0.79 (32484 hom.)
• Consequence: CDK5RAP2 ENST00000483412.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.198
• 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.4726+458C>T		intron_variant	Intron 31 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.4726+458C>T		intron_variant	Intron 31 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123078 AN: 152020 Hom.: 49991 Cov.: 31

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.806

GnomAD4 exome AF: 0.792 AC: 81404 AN: 102832 Hom.: 32484 Cov.: 0 AF XY: 0.793 AC XY: 42798 AN XY: 53974

African (AFR) AF: 0.828 AC: 2999 AN: 3620

American (AMR) AF: 0.879 AC: 4247 AN: 4834

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 1826 AN: 2460

East Asian (EAS) AF: 0.874 AC: 4635 AN: 5306

South Asian (SAS) AF: 0.817 AC: 13109 AN: 16040

European-Finnish (FIN) AF: 0.833 AC: 4046 AN: 4860

Middle Eastern (MID) AF: 0.786 AC: 316 AN: 402

European-Non Finnish (NFE) AF: 0.767 AC: 45857 AN: 59824

Other (OTH) AF: 0.796 AC: 4369 AN: 5486

GnomAD4 genome AF: 0.810 AC: 123176 AN: 152138 Hom.: 50031 Cov.: 31 AF XY: 0.814 AC XY: 60515 AN XY: 74360

African (AFR) AF: 0.830 AC: 34446 AN: 41496

American (AMR) AF: 0.849 AC: 12987 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2609 AN: 3470

East Asian (EAS) AF: 0.875 AC: 4517 AN: 5160

South Asian (SAS) AF: 0.829 AC: 3990 AN: 4814

European-Finnish (FIN) AF: 0.860 AC: 9114 AN: 10594

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52783 AN: 67992

Other (OTH) AF: 0.808 AC: 1706 AN: 2112

Alfa AF: 0.791 Hom.: 167313

Bravo AF: 0.814

Asia WGS AF: 0.886 AC: 3082 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.68
PhyloP100		-0.20
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: rs914592; hg19: chr9-123170167;