rs16909739

Variant names:

• chr9-120403829-A-G
• rs16909739
• NM_018249.6:c.5041+207T>C

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.5041+207T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0559 in 152,292 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.056 (323 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.21
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-120403829-A-G is Benign according to our data. Variant chr9-120403829-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.5041+207T>C		intron_variant	Intron 33 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.5041+207T>C		intron_variant	Intron 33 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8520 AN: 152174 Hom.: 324 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0535

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0946

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0606

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

GnomAD4 genome AF: 0.0559 AC: 8515 AN: 152292 Hom.: 323 Cov.: 32 AF XY: 0.0561 AC XY: 4179 AN XY: 74480

African (AFR) AF: 0.0149 AC: 618 AN: 41560

American (AMR) AF: 0.0535 AC: 818 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0949 AC: 458 AN: 4828

European-Finnish (FIN) AF: 0.0536 AC: 569 AN: 10620

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0822 AC: 5589 AN: 68012

Other (OTH) AF: 0.0600 AC: 127 AN: 2116

Alfa AF: 0.0627 Hom.: 116

Bravo AF: 0.0515

Asia WGS AF: 0.0350 AC: 122 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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	-0.85
CADD	Benign	0.022
DANN	Benign	0.52
PhyloP100		-2.2
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: rs16909739; hg19: chr9-123166107;