9-120407793-G-T

Variant names:

• chr9-120407793-G-T
• rs1888893
• NM_018249.6:c.4727-545C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_018249.6(CDK5RAP2):​c.4727-545C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 180,746 control chromosomes in the GnomAD database, including 31 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 0.014 (31 hom., cov: 29)
  • Exomes 𝑓: 0.0042 (0 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.959
• Publications: 4 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

ENSG00000301087 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2161/151742) while in subpopulation AFR AF = 0.041 (1695/41320). AF 95% confidence interval is 0.0394. There are 31 homozygotes in GnomAd4. There are 1011 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

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.4727-545C>A		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.4724-545C>A		intron	N/A	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.4631-545C>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.4727-545C>A		intron	N/A	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.4726+554C>A		intron	N/A	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000483412.5	TSL:1	n.4588C>A		non_coding_transcript_exon	Exon 24 of 24

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2159 AN: 151630 Hom.: 31 Cov.: 29

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00637

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00644

Gnomad FIN AF: 0.000286

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0111

GnomAD4 exome AF: 0.00417 AC: 121 AN: 29004 Hom.: 0 Cov.: 0 AF XY: 0.00370 AC XY: 56 AN XY: 15130

African (AFR) AF: 0.0322 AC: 17 AN: 528

American (AMR) AF: 0.00573 AC: 19 AN: 3314

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 11 AN: 422

East Asian (EAS) AF: 0.00 AC: 0 AN: 1746

South Asian (SAS) AF: 0.00568 AC: 21 AN: 3696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 922

Middle Eastern (MID) AF: 0.0106 AC: 1 AN: 94

European-Non Finnish (NFE) AF: 0.00255 AC: 43 AN: 16862

Other (OTH) AF: 0.00634 AC: 9 AN: 1420

GnomAD4 genome AF: 0.0142 AC: 2161 AN: 151742 Hom.: 31 Cov.: 29 AF XY: 0.0136 AC XY: 1011 AN XY: 74122

African (AFR) AF: 0.0410 AC: 1695 AN: 41320

American (AMR) AF: 0.00636 AC: 97 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00624 AC: 30 AN: 4806

European-Finnish (FIN) AF: 0.000286 AC: 3 AN: 10478

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 67966

Other (OTH) AF: 0.0109 AC: 23 AN: 2102

Alfa AF: 0.0000420 Hom.: 12556

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.71
PhyloP100		0.96
Mutation Taster		=99/1	polymorphism

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: rs1888893; hg19: chr9-123170071;