chr9-120447847-C-A

Variant names:

• chr9-120447847-C-A
• rs74691300
• NM_018249.6:c.3025+48G>T

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.3025+48G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,316,414 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (51 hom., cov: 32)
  • Exomes 𝑓: 0.026 (485 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.61
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-120447847-C-A is Benign according to our data. Variant chr9-120447847-C-A is described in ClinVar as Benign. ClinVar VariationId is 158136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.3025+48G>T		intron_variant	Intron 22 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.3025+48G>T		intron_variant	Intron 22 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3370 AN: 152196 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0231 AC: 5789 AN: 250492 AF XY: 0.0226

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0378

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0276

GnomAD4 exome AF: 0.0265 AC: 30812 AN: 1164100 Hom.: 485 Cov.: 16 AF XY: 0.0256 AC XY: 15221 AN XY: 593792

African (AFR) AF: 0.00913 AC: 252 AN: 27588

American (AMR) AF: 0.0124 AC: 549 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 364 AN: 24316

East Asian (EAS) AF: 0.0693 AC: 2659 AN: 38386

South Asian (SAS) AF: 0.00721 AC: 579 AN: 80304

European-Finnish (FIN) AF: 0.0360 AC: 1919 AN: 53318

Middle Eastern (MID) AF: 0.0409 AC: 212 AN: 5188

European-Non Finnish (NFE) AF: 0.0274 AC: 23006 AN: 839924

Other (OTH) AF: 0.0251 AC: 1272 AN: 50680

GnomAD4 genome AF: 0.0221 AC: 3372 AN: 152314 Hom.: 51 Cov.: 32 AF XY: 0.0226 AC XY: 1682 AN XY: 74478

African (AFR) AF: 0.00979 AC: 407 AN: 41566

American (AMR) AF: 0.0141 AC: 216 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.0411 AC: 213 AN: 5186

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10614

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0272 AC: 1852 AN: 68028

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0120 Hom.: 9

Bravo AF: 0.0210

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.094
DANN	Benign	0.79
PhyloP100		-2.6
PromoterAI		0.0068	Neutral
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: rs74691300; hg19: chr9-123210125; COSMIC: COSV62576914;