9-120408455-C-G

Variant names:

• chr9-120408455-C-G
• rs4837768
• NM_018249.6:c.4618G>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.4618G>C​(p.Val1540Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 1,613,638 control chromosomes in the GnomAD database, including 462,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39807 hom., cov: 32)
  • Exomes 𝑓: 0.76 (423069 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.0720
• Publications: 37 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 (MetaRNN=8.204581E-7).
• BP6: Variant 9-120408455-C-G is Benign according to our data. Variant chr9-120408455-C-G is described in ClinVar as Benign. ClinVar VariationId is 21651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 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.4618G>C	p.Val1540Leu	missense	Exon 31 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.4615G>C	p.Val1539Leu	missense	Exon 31 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.4522G>C	p.Val1508Leu	missense	Exon 30 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.4618G>C	p.Val1540Leu	missense	Exon 31 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.4618G>C	p.Val1540Leu	missense	Exon 31 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*3442G>C		non_coding_transcript_exon	Exon 32 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.717 AC: 109042 AN: 152000 Hom.: 39799 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.735

GnomAD2 exomes AF: 0.777 AC: 195229 AN: 251218 AF XY: 0.778

Gnomad AFR exome AF: 0.580

Gnomad AMR exome AF: 0.883

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.832

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.753

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.759 AC: 1109893 AN: 1461520 Hom.: 423069 Cov.: 47 AF XY: 0.761 AC XY: 553547 AN XY: 727070

African (AFR) AF: 0.575 AC: 19253 AN: 33474

American (AMR) AF: 0.875 AC: 39125 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 19301 AN: 26134

East Asian (EAS) AF: 0.807 AC: 32029 AN: 39698

South Asian (SAS) AF: 0.823 AC: 71012 AN: 86250

European-Finnish (FIN) AF: 0.784 AC: 41854 AN: 53374

Middle Eastern (MID) AF: 0.743 AC: 4280 AN: 5764

European-Non Finnish (NFE) AF: 0.753 AC: 837644 AN: 1111736

Other (OTH) AF: 0.752 AC: 45395 AN: 60370

GnomAD4 genome AF: 0.717 AC: 109098 AN: 152118 Hom.: 39807 Cov.: 32 AF XY: 0.721 AC XY: 53655 AN XY: 74368

African (AFR) AF: 0.584 AC: 24190 AN: 41436

American (AMR) AF: 0.806 AC: 12339 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2553 AN: 3468

East Asian (EAS) AF: 0.833 AC: 4312 AN: 5176

South Asian (SAS) AF: 0.823 AC: 3973 AN: 4828

European-Finnish (FIN) AF: 0.794 AC: 8407 AN: 10584

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50883 AN: 68008

Other (OTH) AF: 0.733 AC: 1548 AN: 2112

Alfa AF: 0.744 Hom.: 31737

Bravo AF: 0.715

TwinsUK AF: 0.767 AC: 2843

ALSPAC AF: 0.768 AC: 2958

ESP6500AA AF: 0.584 AC: 2574

ESP6500EA AF: 0.753 AC: 6473

ExAC AF: 0.769 AC: 93364

Asia WGS AF: 0.814 AC: 2833 AN: 3478

EpiCase AF: 0.746

EpiControl AF: 0.750

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Microcephaly 3, primary, autosomal recessive (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.8
DANN	Benign	0.85
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		-0.072
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.039
Sift	Benign	0.75	T
Sift4G	Benign	0.12	T
Polyphen		0.0060	B
Vest4		0.078
MutPred		0.11		Loss of MoRF binding (P = 0.0907)
MPC		0.079
ClinPred		0.0068	T
GERP RS		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.031
gMVP		0.062
Mutation Taster		=98/2	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: rs4837768; hg19: chr9-123170733; COSMIC: COSV62571905; COSMIC: COSV62571905;