9-120403882-A-G

Variant names:

• chr9-120403882-A-G
• rs2297453
• NM_018249.6:c.5041+154T>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.5041+154T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,090 control chromosomes in the GnomAD database, including 37,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.70 (37775 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11
• Publications: 7 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=-0.88).
• BP6: Variant 9-120403882-A-G is Benign according to our data. Variant chr9-120403882-A-G is described in ClinVar as Benign. ClinVar VariationId is 678320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.5041+154T>C		intron_variant	Intron 33 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.5041+154T>C		intron_variant	Intron 33 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106766 AN: 151972 Hom.: 37760 Cov.: 32

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.708

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.716

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

GnomAD4 genome AF: 0.702 AC: 106837 AN: 152090 Hom.: 37775 Cov.: 32 AF XY: 0.702 AC XY: 52207 AN XY: 74360

African (AFR) AF: 0.647 AC: 26806 AN: 41446

American (AMR) AF: 0.731 AC: 11176 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 2454 AN: 3466

East Asian (EAS) AF: 0.562 AC: 2903 AN: 5166

South Asian (SAS) AF: 0.726 AC: 3504 AN: 4826

European-Finnish (FIN) AF: 0.742 AC: 7858 AN: 10596

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.732 AC: 49746 AN: 67986

Other (OTH) AF: 0.717 AC: 1509 AN: 2106

Alfa AF: 0.716 Hom.: 22724

Bravo AF: 0.704

Asia WGS AF: 0.651 AC: 2265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.74
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2297453; hg19: chr9-123166160;