chr9-120518659-C-T

Position:

• chr9-120518659-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018249.6(CDK5RAP2):​c.1093-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,608,532 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (57 hom., cov: 29)
  • Exomes 𝑓: 0.028 (676 hom.)
• Consequence: CDK5RAP2 NM_018249.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0770

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-120518659-C-T is Benign according to our data. Variant chr9-120518659-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120518659-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3245/151878) while in subpopulation NFE AF= 0.0291 (1975/67946). AF 95% confidence interval is 0.028. There are 57 homozygotes in gnomad4. There are 1686 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.1093-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.1093-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3243 AN: 151760 Hom.: 57 Cov.: 29

Gnomad AFR AF: 0.00506

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0238 AC: 5972 AN: 251054 Hom.: 86 AF XY: 0.0246 AC XY: 3342 AN XY: 135682

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.00760

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0284 AC: 41338 AN: 1456654 Hom.: 676 Cov.: 29 AF XY: 0.0286 AC XY: 20733 AN XY: 725094

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.00749

Gnomad4 ASJ exome AF: 0.00808

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.0557

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0246

GnomAD4 genome AF: 0.0214 AC: 3245 AN: 151878 Hom.: 57 Cov.: 29 AF XY: 0.0227 AC XY: 1686 AN XY: 74230

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.0606

Gnomad4 NFE AF: 0.0291

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.0235 Hom.: 10

Bravo AF: 0.0167

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Primary Microcephaly, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs75029577; hg19: chr9-123280937;