NM_018249.6:c.3134G>C

Variant names:

• chr9-120443634-C-G
• rs3780679
• NM_018249.6:c.3134G>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.3134G>C​(p.Arg1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,972 control chromosomes in the GnomAD database, including 2,029 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1045K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.073 (773 hom., cov: 33)
  • Exomes 𝑓: 0.032 (1256 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.31
• Publications: 21 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=0.0011312366).
• BP6: Variant 9-120443634-C-G is Benign according to our data. Variant chr9-120443634-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 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.3134G>C	p.Arg1045Thr	missense	Exon 23 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.3131G>C	p.Arg1044Thr	missense	Exon 23 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.3038G>C	p.Arg1013Thr	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.3134G>C	p.Arg1045Thr	missense	Exon 23 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.3134G>C	p.Arg1045Thr	missense	Exon 23 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*1958G>C		non_coding_transcript_exon	Exon 24 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11100 AN: 152124 Hom.: 767 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0369 AC: 9282 AN: 251322 AF XY: 0.0326

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0235

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0383

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0356

GnomAD4 exome AF: 0.0320 AC: 46716 AN: 1461730 Hom.: 1256 Cov.: 32 AF XY: 0.0306 AC XY: 22217 AN XY: 727170

African (AFR) AF: 0.186 AC: 6223 AN: 33466

American (AMR) AF: 0.0249 AC: 1112 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 391 AN: 26134

East Asian (EAS) AF: 0.0685 AC: 2717 AN: 39686

South Asian (SAS) AF: 0.00750 AC: 647 AN: 86258

European-Finnish (FIN) AF: 0.0359 AC: 1916 AN: 53410

Middle Eastern (MID) AF: 0.0496 AC: 286 AN: 5766

European-Non Finnish (NFE) AF: 0.0280 AC: 31082 AN: 1111896

Other (OTH) AF: 0.0388 AC: 2342 AN: 60390

GnomAD4 genome AF: 0.0731 AC: 11135 AN: 152242 Hom.: 773 Cov.: 33 AF XY: 0.0727 AC XY: 5409 AN XY: 74444

African (AFR) AF: 0.185 AC: 7670 AN: 41512

American (AMR) AF: 0.0375 AC: 574 AN: 15296

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

East Asian (EAS) AF: 0.0411 AC: 213 AN: 5178

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4826

European-Finnish (FIN) AF: 0.0413 AC: 438 AN: 10608

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0279 AC: 1901 AN: 68030

Other (OTH) AF: 0.0581 AC: 123 AN: 2116

Alfa AF: 0.0310 Hom.: 145

Bravo AF: 0.0797

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.182 AC: 801

ESP6500EA AF: 0.0297 AC: 255

ExAC AF: 0.0408 AC: 4948

Asia WGS AF: 0.0670 AC: 231 AN: 3478

EpiCase AF: 0.0270

EpiControl AF: 0.0301

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)
-	-	-	Microcephaly 3, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.067
MPC		0.11
ClinPred		0.0033	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.069
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: rs3780679; hg19: chr9-123205912; COSMIC: COSV62574101; COSMIC: COSV62574101;