17-47975970-G-A

Variant names:

• chr17-47975970-G-A
• rs746686583
• NM_176096.3:c.755G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176096.3(CDK5RAP3):​c.755G>A​(p.Arg252Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDK5RAP3 NM_176096.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76
• Publications: 4 publications found

Genes affected

CDK5RAP3 (HGNC:18673): (CDK5 regulatory subunit associated protein 3) This gene encodes a protein that has been reported to function in signaling pathways governing transcriptional regulation and cell cycle progression. It may play a role in tumorigenesis and metastasis. A pseudogene of this gene is located on the long arm of chromosome 20. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, May 2013]

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3647244).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176096.3. 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
	CDK5RAP3	NM_176096.3	MANE Select	c.755G>A	p.Arg252Gln	missense	Exon 8 of 14	NP_788276.1	Q96JB5-1
	CDK5RAP3	NM_001278197.2		c.830G>A	p.Arg277Gln	missense	Exon 8 of 14	NP_001265126.1	Q96JB5-4
	CDK5RAP3	NM_001278217.2		c.494G>A	p.Arg165Gln	missense	Exon 7 of 13	NP_001265146.1	Q96JB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP3	ENST00000338399.9	TSL:1 MANE Select	c.755G>A	p.Arg252Gln	missense	Exon 8 of 14	ENSP00000344683.4	Q96JB5-1
	CDK5RAP3	ENST00000580287.5	TSL:1	n.1700G>A		non_coding_transcript_exon	Exon 6 of 13
	CDK5RAP3	ENST00000584063.5	TSL:1	n.1723G>A		non_coding_transcript_exon	Exon 6 of 12

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249458 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461836 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727210

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0085	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.16
Sift	Benign	0.047	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.48
MutPred		0.42		Loss of helix (P = 0.1706)
MVP		0.73
MPC		0.35
ClinPred		0.64	D
GERP RS		4.2
Varity_R		0.070
gMVP		0.52
Mutation Taster		=84/16	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: rs746686583; hg19: chr17-46053336; COSMIC: COSV58114545; COSMIC: COSV58114545;