rs144723485

chr9-120453681-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_018249.6(CDK5RAP2):c.2568G>A(p.Gln856=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,202 control chromosomes in the GnomAD database, including 5 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 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: CDK5RAP2 NM_018249.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-120453681-C-T is Benign according to our data. Variant chr9-120453681-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 364765.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=3}.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00157 (239/152310) while in subpopulation AMR AF= 0.00457 (70/15304). AF 95% confidence interval is 0.00371. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.2568G>A	p.Gln856=	synonymous_variant	21/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.2568G>A	p.Gln856=	synonymous_variant	21/38	1	NM_018249.6	P4

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00152 AC: 383 AN: 251424 Hom.: 2 AF XY: 0.00156 AC XY: 212 AN XY: 135880

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00110 AC: 1615 AN: 1461892 Hom.: 5 Cov.: 32 AF XY: 0.00114 AC XY: 831 AN XY: 727248

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74492

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00161

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00234

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CDK5RAP2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Primary Microcephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 24, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.2
Dann	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs144723485; hg19: chr9-123215959; COSMIC: COSV62574838;