rs2297457

Variant names:

• chr9-120389821-C-G
• rs2297457
• NM_018249.6:c.5579-34G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-120389821-C-G
• chr9-120389821-C-A
• chr9-120389821-C-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.5579-34G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 1,603,718 control chromosomes in the GnomAD database, including 389,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38705 hom., cov: 32)
  • Exomes 𝑓: 0.69 (351213 hom.)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.832
• Publications: 9 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.94).
• BP6: Variant 9-120389821-C-G is Benign according to our data. Variant chr9-120389821-C-G is described in ClinVar as Benign. ClinVar VariationId is 158168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	NM_018249.6	MANE Select	c.5579-34G>C		intron	N/A	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.5576-34G>C		intron	N/A	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.5483-34G>C		intron	N/A	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.5579-34G>C		intron	N/A	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.5342-34G>C		intron	N/A	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*4403-34G>C		intron	N/A	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108190 AN: 152056 Hom.: 38664 Cov.: 32

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.709

GnomAD2 exomes AF: 0.717 AC: 179761 AN: 250576 AF XY: 0.710

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.657

Gnomad EAS exome AF: 0.795

Gnomad FIN exome AF: 0.767

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.717

GnomAD4 exome AF: 0.694 AC: 1007923 AN: 1451544 Hom.: 351213 Cov.: 28 AF XY: 0.693 AC XY: 500952 AN XY: 722778

African (AFR) AF: 0.735 AC: 24417 AN: 33238

American (AMR) AF: 0.793 AC: 35411 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 17157 AN: 26068

East Asian (EAS) AF: 0.786 AC: 31162 AN: 39638

South Asian (SAS) AF: 0.668 AC: 57490 AN: 86012

European-Finnish (FIN) AF: 0.768 AC: 41003 AN: 53374

Middle Eastern (MID) AF: 0.677 AC: 3886 AN: 5740

European-Non Finnish (NFE) AF: 0.685 AC: 755783 AN: 1102800

Other (OTH) AF: 0.693 AC: 41614 AN: 60012

GnomAD4 genome AF: 0.712 AC: 108289 AN: 152174 Hom.: 38705 Cov.: 32 AF XY: 0.715 AC XY: 53188 AN XY: 74388

African (AFR) AF: 0.733 AC: 30424 AN: 41512

American (AMR) AF: 0.749 AC: 11455 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2248 AN: 3468

East Asian (EAS) AF: 0.799 AC: 4138 AN: 5182

South Asian (SAS) AF: 0.670 AC: 3225 AN: 4816

European-Finnish (FIN) AF: 0.776 AC: 8226 AN: 10596

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46376 AN: 68002

Other (OTH) AF: 0.709 AC: 1499 AN: 2114

Alfa AF: 0.639 Hom.: 3966

Bravo AF: 0.715

Asia WGS AF: 0.770 AC: 2676 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephaly 3, primary, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.25
DANN	Benign	0.44
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2297457; hg19: chr9-123152099; COSMIC: COSV62574193;