NM_018249.6:c.3955+4437C>G

Variant names:

• chr9-120432858-G-C
• rs944642
• NM_018249.6:c.3955+4437C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018249.6(CDK5RAP2):​c.3955+4437C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,270 control chromosomes in the GnomAD database, including 1,570 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1570 hom., cov: 32)
• Consequence: CDK5RAP2 NM_018249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.563
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• corpus callosum, agenesis of

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6	c.3955+4437C>G		intron_variant	Intron 25 of 37	ENST00000349780.9	NP_060719.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9	c.3955+4437C>G		intron_variant	Intron 25 of 37	1	NM_018249.6	ENSP00000343818.4

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16408 AN: 152152 Hom.: 1552 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0974

Gnomad OTH AF: 0.127

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.108 AC: 16441 AN: 152270 Hom.: 1570 Cov.: 32 AF XY: 0.115 AC XY: 8577 AN XY: 74458

African (AFR) AF: 0.0229 AC: 951 AN: 41582

American (AMR) AF: 0.258 AC: 3944 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.375 AC: 1944 AN: 5180

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4822

European-Finnish (FIN) AF: 0.120 AC: 1271 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0974 AC: 6621 AN: 67992

Other (OTH) AF: 0.131 AC: 276 AN: 2114

Alfa AF: 0.0464 Hom.: 31

Bravo AF: 0.118

Asia WGS AF: 0.266 AC: 920 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.5
DANN	Benign	0.68
PhyloP100		0.56
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: rs944642; hg19: chr9-123195136;