chr9-120389372-G-A

Variant names:

• chr9-120389372-G-A
• rs76452024
• NM_018249.6:c.5626-80C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018249.6(CDK5RAP2):​c.5626-80C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,114,690 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0085 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.75
• Publications: 1 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=-0.93).
• BP6: Variant 9-120389372-G-A is Benign according to our data. Variant chr9-120389372-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1218482.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00851 (1296/152278) while in subpopulation AFR AF = 0.0292 (1214/41558). AF 95% confidence interval is 0.0278. There are 21 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.5626-80C>T		intron_variant	Intron 37 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.5626-80C>T		intron_variant	Intron 37 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.00846 AC: 1288 AN: 152160 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00115 AC: 1105 AN: 962412 Hom.: 22 AF XY: 0.00108 AC XY: 533 AN XY: 494060

African (AFR) AF: 0.0342 AC: 792 AN: 23164

American (AMR) AF: 0.00222 AC: 81 AN: 36464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22502

East Asian (EAS) AF: 0.00 AC: 0 AN: 34504

South Asian (SAS) AF: 0.000914 AC: 65 AN: 71090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45118

Middle Eastern (MID) AF: 0.00248 AC: 12 AN: 4840

European-Non Finnish (NFE) AF: 0.0000382 AC: 26 AN: 681044

Other (OTH) AF: 0.00295 AC: 129 AN: 43686

GnomAD4 genome AF: 0.00851 AC: 1296 AN: 152278 Hom.: 21 Cov.: 33 AF XY: 0.00841 AC XY: 626 AN XY: 74462

African (AFR) AF: 0.0292 AC: 1214 AN: 41558

American (AMR) AF: 0.00320 AC: 49 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00770 Hom.: 1

Bravo AF: 0.0101

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 15, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.021
DANN	Benign	0.50
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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: rs76452024; hg19: chr9-123151650;