rs4836822

Variant names:

• chr9-120528758-C-G
• rs4836822
• NM_018249.6:c.865G>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.865G>C​(p.Glu289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,606,270 control chromosomes in the GnomAD database, including 661,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (55080 hom., cov: 32)
  • Exomes 𝑓: 0.91 (606530 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 2.64
• Publications: 42 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.7629204E-7).
• BP6: Variant 9-120528758-C-G is Benign according to our data. Variant chr9-120528758-C-G is described in ClinVar as Benign. ClinVar VariationId is 21657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.922 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.865G>C	p.Glu289Gln	missense	Exon 9 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.865G>C	p.Glu289Gln	missense	Exon 9 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.865G>C	p.Glu289Gln	missense	Exon 9 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.865G>C	p.Glu289Gln	missense	Exon 9 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.865G>C	p.Glu289Gln	missense	Exon 9 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.862G>C		non_coding_transcript_exon	Exon 9 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128226 AN: 152030 Hom.: 55063 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.866

GnomAD2 exomes AF: 0.879 AC: 220722 AN: 251222 AF XY: 0.885

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.721

Gnomad FIN exome AF: 0.929

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.903

GnomAD4 exome AF: 0.912 AC: 1325495 AN: 1454122 Hom.: 606530 Cov.: 33 AF XY: 0.912 AC XY: 659984 AN XY: 723976

African (AFR) AF: 0.676 AC: 22504 AN: 33302

American (AMR) AF: 0.856 AC: 38281 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 24251 AN: 26078

East Asian (EAS) AF: 0.714 AC: 28301 AN: 39656

South Asian (SAS) AF: 0.881 AC: 75852 AN: 86070

European-Finnish (FIN) AF: 0.926 AC: 49453 AN: 53408

Middle Eastern (MID) AF: 0.910 AC: 5228 AN: 5744

European-Non Finnish (NFE) AF: 0.930 AC: 1028037 AN: 1105006

Other (OTH) AF: 0.891 AC: 53588 AN: 60160

GnomAD4 genome AF: 0.843 AC: 128284 AN: 152148 Hom.: 55080 Cov.: 32 AF XY: 0.843 AC XY: 62682 AN XY: 74368

African (AFR) AF: 0.681 AC: 28213 AN: 41440

American (AMR) AF: 0.856 AC: 13093 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3225 AN: 3470

East Asian (EAS) AF: 0.712 AC: 3687 AN: 5182

South Asian (SAS) AF: 0.871 AC: 4196 AN: 4818

European-Finnish (FIN) AF: 0.923 AC: 9792 AN: 10604

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.928 AC: 63117 AN: 68024

Other (OTH) AF: 0.865 AC: 1828 AN: 2114

Alfa AF: 0.909 Hom.: 47736

Bravo AF: 0.831

TwinsUK AF: 0.939 AC: 3480

ALSPAC AF: 0.934 AC: 3600

ESP6500AA AF: 0.693 AC: 3053

ESP6500EA AF: 0.928 AC: 7981

ExAC AF: 0.877 AC: 106466

Asia WGS AF: 0.753 AC: 2619 AN: 3478

EpiCase AF: 0.927

EpiControl AF: 0.928

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	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	7.8e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.90	P
Vest4		0.23
MPC		0.18
ClinPred		0.026	T
GERP RS		4.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.13
gMVP		0.22
Mutation Taster		=96/4	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: rs4836822; hg19: chr9-123291036; COSMIC: COSV62573846;