rs114128928

Positions:

• chr9-120394636-A-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 -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 id is 158164.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr9-120394636-A-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5RAP2	NM_018249.6	c.5454T>G	p.Ile1818Met	missense_variant, splice_region_variant	36/38	ENST00000349780.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.5454T>G	p.Ile1818Met	missense_variant, splice_region_variant	36/38	1	NM_018249.6	P4

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

GnomAD3 exomes AF: 0.00147 AC: 368 AN: 251172 Hom.: 4 AF XY: 0.00110 AC XY: 150 AN XY: 135806

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000812

Gnomad4 OTH exome AF: 0.00159

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

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00135 Hom.: 1

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2019	- -
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

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	.;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.26	.;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.031, 0.0020, 0.015	.;B;B;B;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

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: rs114128928; hg19: chr9-123156914;