9-120389401-A-G

Variant names:

• chr9-120389401-A-G
• rs4836820
• NM_018249.6:c.5626-109T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018249.6(CDK5RAP2):​c.5626-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 866,718 control chromosomes in the GnomAD database, including 236,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45243 hom., cov: 33)
  • Exomes 𝑓: 0.73 (191015 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.106
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-120389401-A-G is Benign according to our data. Variant chr9-120389401-A-G is described in ClinVar as Benign. ClinVar VariationId is 678323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.849 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.5626-109T>C		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.5623-109T>C		intron	N/A	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.5530-109T>C		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.5626-109T>C		intron	N/A	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.5389-109T>C		intron	N/A	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*4450-109T>C		intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116737 AN: 152100 Hom.: 45182 Cov.: 33

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.710

Gnomad OTH AF: 0.754

GnomAD4 exome AF: 0.729 AC: 520877 AN: 714500 Hom.: 191015 AF XY: 0.725 AC XY: 273336 AN XY: 376966

African (AFR) AF: 0.859 AC: 15915 AN: 18534

American (AMR) AF: 0.814 AC: 28272 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 14337 AN: 20984

East Asian (EAS) AF: 0.865 AC: 28352 AN: 32772

South Asian (SAS) AF: 0.676 AC: 44310 AN: 65526

European-Finnish (FIN) AF: 0.804 AC: 31811 AN: 39590

Middle Eastern (MID) AF: 0.730 AC: 3189 AN: 4366

European-Non Finnish (NFE) AF: 0.711 AC: 328473 AN: 462292

Other (OTH) AF: 0.735 AC: 26218 AN: 35686

GnomAD4 genome AF: 0.768 AC: 116857 AN: 152218 Hom.: 45243 Cov.: 33 AF XY: 0.771 AC XY: 57341 AN XY: 74406

African (AFR) AF: 0.856 AC: 35556 AN: 41534

American (AMR) AF: 0.781 AC: 11944 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2349 AN: 3470

East Asian (EAS) AF: 0.843 AC: 4369 AN: 5184

South Asian (SAS) AF: 0.675 AC: 3257 AN: 4824

European-Finnish (FIN) AF: 0.820 AC: 8684 AN: 10596

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.710 AC: 48269 AN: 67998

Other (OTH) AF: 0.757 AC: 1598 AN: 2112

Alfa AF: 0.735 Hom.: 10574

Bravo AF: 0.774

Asia WGS AF: 0.816 AC: 2838 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		0.11
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: rs4836820; hg19: chr9-123151679; COSMIC: COSV62578562;