rs10984922

Variant names:

• chr9-120472144-C-T
• rs10984922
• NM_018249.6:c.1728-266G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018249.6(CDK5RAP2):​c.1728-266G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,238 control chromosomes in the GnomAD database, including 1,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1273 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.263
• Publications: 13 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-120472144-C-T is Benign according to our data. Variant chr9-120472144-C-T is described in ClinVar as Benign. ClinVar VariationId is 674221.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.1728-266G>A		intron_variant	Intron 15 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.1728-266G>A		intron_variant	Intron 15 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18002 AN: 152120 Hom.: 1274 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.118 AC: 18004 AN: 152238 Hom.: 1273 Cov.: 32 AF XY: 0.117 AC XY: 8711 AN XY: 74426

African (AFR) AF: 0.0615 AC: 2556 AN: 41548

American (AMR) AF: 0.100 AC: 1537 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 511 AN: 3472

East Asian (EAS) AF: 0.0421 AC: 218 AN: 5184

South Asian (SAS) AF: 0.0621 AC: 300 AN: 4828

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10590

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10756 AN: 68002

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.141 Hom.: 4755

Bravo AF: 0.112

Asia WGS AF: 0.0670 AC: 234 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.91
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.26
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: rs10984922; hg19: chr9-123234422; COSMIC: COSV62573101;