NM_018249.6:c.4414+771C>T

Variant names:

• chr9-120410587-G-A
• rs7853439
• NM_018249.6:c.4414+771C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018249.6(CDK5RAP2):​c.4414+771C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 152,062 control chromosomes in the GnomAD database, including 11,528 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 0.36 (11528 hom., cov: 33)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 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.4414+771C>T		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.4411+771C>T		intron	N/A	NP_001397923.1
	CDK5RAP2	NM_001410993.1		c.4318+771C>T		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.4414+771C>T		intron	N/A	ENSP00000343818.4
	CDK5RAP2	ENST00000360190.8	TSL:1	c.4414+771C>T		intron	N/A	ENSP00000353317.4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*3238+771C>T		intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55134 AN: 151944 Hom.: 11501 Cov.: 33

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.347

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

GnomAD4 genome AF: 0.363 AC: 55214 AN: 152062 Hom.: 11528 Cov.: 33 AF XY: 0.363 AC XY: 26949 AN XY: 74314

African (AFR) AF: 0.584 AC: 24220 AN: 41470

American (AMR) AF: 0.335 AC: 5126 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 949 AN: 3472

East Asian (EAS) AF: 0.352 AC: 1818 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1489 AN: 4814

European-Finnish (FIN) AF: 0.264 AC: 2790 AN: 10560

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17623 AN: 67982

Other (OTH) AF: 0.349 AC: 735 AN: 2106

Alfa AF: 0.350 Hom.: 2041

Bravo AF: 0.378

Asia WGS AF: 0.382 AC: 1331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.2
DANN	Benign	0.66
PhyloP100		1.5
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: rs7853439; hg19: chr9-123172865;