rs114128928

Variant names:

• chr9-120394636-A-C
• rs114128928
• NM_018249.6:c.5454T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018249.6(CDK5RAP2):​c.5454T>G​(p.Ile1818Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,609,274 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.677
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036321282).
• BP6: Variant 9-120394636-A-C is Benign according to our data. Variant chr9-120394636-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158164.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0057 (868/152318) while in subpopulation AFR AF = 0.0198 (822/41566). AF 95% confidence interval is 0.0187. There are 8 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.5454T>G	p.Ile1818Met	missense splice_region	Exon 36 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.5451T>G	p.Ile1817Met	missense splice_region	Exon 36 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.5358T>G	p.Ile1786Met	missense splice_region	Exon 35 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.5454T>G	p.Ile1818Met	missense splice_region	Exon 36 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.5217T>G	p.Ile1739Met	missense splice_region	Exon 35 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*4278T>G		splice_region non_coding_transcript_exon	Exon 37 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 865 AN: 152200 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00147 AC: 368 AN: 251172 AF XY: 0.00110

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000648 AC: 944 AN: 1456956 Hom.: 4 Cov.: 31 AF XY: 0.000556 AC XY: 403 AN XY: 725206

African (AFR) AF: 0.0205 AC: 685 AN: 33366

American (AMR) AF: 0.00116 AC: 52 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5756

European-Non Finnish (NFE) AF: 0.0000812 AC: 90 AN: 1107840

Other (OTH) AF: 0.00159 AC: 96 AN: 60226

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152318 Hom.: 8 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74490

African (AFR) AF: 0.0198 AC: 822 AN: 41566

American (AMR) AF: 0.00183 AC: 28 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00265 Hom.: 5

Bravo AF: 0.00652

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.68
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.043
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.031	B
Vest4		0.18
MVP		0.21
MPC		0.40
ClinPred		0.013	T
GERP RS		0.075
Varity_R		0.049
gMVP		0.065
Mutation Taster		=98/2	polymorphism

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: rs114128928; hg19: chr9-123156914;