NM_018249.6:c.5578+133A>C

Variant names:

• chr9-120394379-T-G
• rs10984901
• NM_018249.6:c.5578+133A>C

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.5578+133A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,401,658 control chromosomes in the GnomAD database, including 97,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (8431 hom., cov: 32)
  • Exomes 𝑓: 0.37 (89273 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-120394379-T-G is Benign according to our data. Variant chr9-120394379-T-G is described in ClinVar as Benign. ClinVar VariationId is 678330.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.45 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.5578+133A>C		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.5575+133A>C		intron	N/A	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.5482+133A>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.5578+133A>C		intron	N/A	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.5341+133A>C		intron	N/A	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*4402+133A>C		intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45805 AN: 151888 Hom.: 8421 Cov.: 32

Gnomad AFR AF: 0.0895

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.371 AC: 464201 AN: 1249652 Hom.: 89273 AF XY: 0.374 AC XY: 235338 AN XY: 629390

African (AFR) AF: 0.0762 AC: 2212 AN: 29030

American (AMR) AF: 0.492 AC: 18854 AN: 38304

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 7514 AN: 23812

East Asian (EAS) AF: 0.439 AC: 16875 AN: 38408

South Asian (SAS) AF: 0.454 AC: 35560 AN: 78342

European-Finnish (FIN) AF: 0.461 AC: 18785 AN: 40786

Middle Eastern (MID) AF: 0.252 AC: 1142 AN: 4526

European-Non Finnish (NFE) AF: 0.365 AC: 344632 AN: 942948

Other (OTH) AF: 0.348 AC: 18627 AN: 53496

GnomAD4 genome AF: 0.301 AC: 45824 AN: 152006 Hom.: 8431 Cov.: 32 AF XY: 0.311 AC XY: 23107 AN XY: 74312

African (AFR) AF: 0.0894 AC: 3708 AN: 41494

American (AMR) AF: 0.394 AC: 6024 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1046 AN: 3466

East Asian (EAS) AF: 0.445 AC: 2287 AN: 5136

South Asian (SAS) AF: 0.466 AC: 2239 AN: 4804

European-Finnish (FIN) AF: 0.482 AC: 5088 AN: 10564

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24397 AN: 67954

Other (OTH) AF: 0.315 AC: 662 AN: 2104

Alfa AF: 0.237 Hom.: 2419

Bravo AF: 0.288

Asia WGS AF: 0.420 AC: 1459 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.66
DANN	Benign	0.69
PhyloP100		-1.3
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: rs10984901; hg19: chr9-123156657; COSMIC: COSV62573853; COSMIC: COSV62573853;