rs6478475

Variant names:

• chr9-120419924-C-T
• rs6478475
• NM_018249.6:c.4041G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-120419924-C-T
• chr9-120419924-C-A
• chr9-120419924-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018249.6(CDK5RAP2):​c.4041G>A​(p.Leu1347Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,613,676 control chromosomes in the GnomAD database, including 2,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1149 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1569 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.26
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-120419924-C-T is Benign according to our data. Variant chr9-120419924-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 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.4041G>A	p.Leu1347Leu	synonymous	Exon 27 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.4038G>A	p.Leu1346Leu	synonymous	Exon 27 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.3945G>A	p.Leu1315Leu	synonymous	Exon 26 of 37	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.4041G>A	p.Leu1347Leu	synonymous	Exon 27 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.4041G>A	p.Leu1347Leu	synonymous	Exon 27 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*2865G>A		non_coding_transcript_exon	Exon 28 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12903 AN: 152064 Hom.: 1141 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0636

GnomAD2 exomes AF: 0.0400 AC: 10058 AN: 251472 AF XY: 0.0349

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0331 AC: 48307 AN: 1461494 Hom.: 1569 Cov.: 31 AF XY: 0.0315 AC XY: 22884 AN XY: 727062

African (AFR) AF: 0.229 AC: 7658 AN: 33456

American (AMR) AF: 0.0273 AC: 1222 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 457 AN: 26132

East Asian (EAS) AF: 0.0692 AC: 2748 AN: 39690

South Asian (SAS) AF: 0.00764 AC: 659 AN: 86254

European-Finnish (FIN) AF: 0.0359 AC: 1918 AN: 53420

Middle Eastern (MID) AF: 0.0522 AC: 301 AN: 5768

European-Non Finnish (NFE) AF: 0.0277 AC: 30788 AN: 1111674

Other (OTH) AF: 0.0423 AC: 2556 AN: 60376

GnomAD4 genome AF: 0.0851 AC: 12949 AN: 152182 Hom.: 1149 Cov.: 33 AF XY: 0.0840 AC XY: 6248 AN XY: 74398

African (AFR) AF: 0.226 AC: 9367 AN: 41482

American (AMR) AF: 0.0423 AC: 647 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.0419 AC: 217 AN: 5174

South Asian (SAS) AF: 0.00685 AC: 33 AN: 4820

European-Finnish (FIN) AF: 0.0413 AC: 438 AN: 10598

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0281 AC: 1909 AN: 68022

Other (OTH) AF: 0.0682 AC: 144 AN: 2112

Alfa AF: 0.0434 Hom.: 607

Bravo AF: 0.0930

Asia WGS AF: 0.0720 AC: 249 AN: 3478

EpiCase AF: 0.0272

EpiControl AF: 0.0299

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.48
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6478475; hg19: chr9-123182202; COSMIC: COSV62576900;