rs34523498

Variant names:

• chr9-120443703-C-T
• rs34523498
• NM_018249.6:c.3065G>A

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.3065G>A​(p.Gly1022Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,614,004 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (80 hom., cov: 33)
  • Exomes 𝑓: 0.027 (624 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.567
• Publications: 22 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=0.001809448).
• BP6: Variant 9-120443703-C-T is Benign according to our data. Variant chr9-120443703-C-T is described in ClinVar as Benign. ClinVar VariationId is 21645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0658 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.3065G>A	p.Gly1022Glu	missense	Exon 23 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.3062G>A	p.Gly1021Glu	missense	Exon 23 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.2969G>A	p.Gly990Glu	missense	Exon 22 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.3065G>A	p.Gly1022Glu	missense	Exon 23 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.3065G>A	p.Gly1022Glu	missense	Exon 23 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*1889G>A		non_coding_transcript_exon	Exon 24 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4408 AN: 152136 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0408

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0250 AC: 6273 AN: 251176 AF XY: 0.0240

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0378

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0273 AC: 39917 AN: 1461750 Hom.: 624 Cov.: 32 AF XY: 0.0266 AC XY: 19328 AN XY: 727176

African (AFR) AF: 0.0331 AC: 1109 AN: 33476

American (AMR) AF: 0.0135 AC: 605 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 390 AN: 26132

East Asian (EAS) AF: 0.0680 AC: 2698 AN: 39694

South Asian (SAS) AF: 0.00710 AC: 612 AN: 86256

European-Finnish (FIN) AF: 0.0359 AC: 1916 AN: 53408

Middle Eastern (MID) AF: 0.0406 AC: 234 AN: 5766

European-Non Finnish (NFE) AF: 0.0276 AC: 30737 AN: 1111906

Other (OTH) AF: 0.0268 AC: 1616 AN: 60388

GnomAD4 genome AF: 0.0290 AC: 4418 AN: 152254 Hom.: 80 Cov.: 33 AF XY: 0.0293 AC XY: 2184 AN XY: 74420

African (AFR) AF: 0.0339 AC: 1408 AN: 41538

American (AMR) AF: 0.0160 AC: 244 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.0409 AC: 212 AN: 5182

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4816

European-Finnish (FIN) AF: 0.0413 AC: 438 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1859 AN: 68030

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0281 Hom.: 189

Bravo AF: 0.0287

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.0290 AC: 249

ExAC AF: 0.0263 AC: 3191

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.57
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.027
Sift	Uncertain	0.024	D
Sift4G	Benign	0.40	T
Polyphen		0.053	B
Vest4		0.15
MPC		0.48
ClinPred		0.0062	T
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.086
gMVP		0.10
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: rs34523498; hg19: chr9-123205981; COSMIC: COSV62574106; COSMIC: COSV62574106;