rs146736925

Variant names:

• chr9-120439563-G-A
• rs146736925
• NM_018249.6:c.3558C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_018249.6(CDK5RAP2):​c.3558C>T​(p.Leu1186Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.392
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-120439563-G-A is Benign according to our data. Variant chr9-120439563-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210635.
• BP7: Synonymous conserved (PhyloP=-0.392 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000958 (146/152332) while in subpopulation AFR AF = 0.00339 (141/41576). AF 95% confidence interval is 0.00294. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3558C>T	p.Leu1186Leu	synonymous	Exon 24 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.3555C>T	p.Leu1185Leu	synonymous	Exon 24 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.3462C>T	p.Leu1154Leu	synonymous	Exon 23 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.3558C>T	p.Leu1186Leu	synonymous	Exon 24 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.3558C>T	p.Leu1186Leu	synonymous	Exon 24 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*2382C>T		non_coding_transcript_exon	Exon 25 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000314 AC: 79 AN: 251200 AF XY: 0.000214

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1461872 Hom.: 1 Cov.: 33 AF XY: 0.000135 AC XY: 98 AN XY: 727234

African (AFR) AF: 0.00445 AC: 149 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112000

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74490

African (AFR) AF: 0.00339 AC: 141 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	CDK5RAP2-related disorder (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.0
DANN	Benign	0.67
PhyloP100		-0.39

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: rs146736925; hg19: chr9-123201841;