chr20-33367001-C-T

Variant names:

• chr20-33367001-C-T
• rs754826757
• NM_016408.4:c.1400G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016408.4(CDK5RAP1):​c.1400G>A​(p.Arg467Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,597,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CDK5RAP1 NM_016408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

Genes affected

CDK5RAP1 (HGNC:15880): (CDK5 regulatory subunit associated protein 1) This gene encodes a regulator of cyclin-dependent kinase 5 activity. This protein has also been reported to modify RNA by adding a methylthio-group and may thus have a dual function as an RNA methylthiotransferase and as an inhibitor of cyclin-dependent kinase 5 activity. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20380801).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016408.4. 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
	CDK5RAP1	NM_016408.4	MANE Select	c.1400G>A	p.Arg467Gln	missense	Exon 12 of 14	NP_057492.2
	CDK5RAP1	NM_001365728.1		c.1442G>A	p.Arg481Gln	missense	Exon 13 of 15	NP_001352657.1	Q96SZ6-1
	CDK5RAP1	NM_016082.4		c.1403G>A	p.Arg468Gln	missense	Exon 12 of 14	NP_057166.4	Q96SZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP1	ENST00000346416.7	TSL:1 MANE Select	c.1400G>A	p.Arg467Gln	missense	Exon 12 of 14	ENSP00000217372.2	Q96SZ6-3
	CDK5RAP1	ENST00000339269.5	TSL:1	c.1169G>A	p.Arg390Gln	missense	Exon 11 of 13	ENSP00000341840.5	Q96SZ6-4
	CDK5RAP1	ENST00000874266.1		c.1493G>A	p.Arg498Gln	missense	Exon 13 of 15	ENSP00000544325.1

Frequencies

GnomAD3 genomes AF: 0.0000596 AC: 9 AN: 151044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000177 AC: 4 AN: 225878 AF XY: 0.0000163

Gnomad AFR exome AF: 0.0000635

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: 0.0000283

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000401 AC: 58 AN: 1446494 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 29 AN XY: 719566

African (AFR) AF: 0.0000312 AC: 1 AN: 32074

American (AMR) AF: 0.00 AC: 0 AN: 40348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 82778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.0000515 AC: 57 AN: 1107612

Other (OTH) AF: 0.00 AC: 0 AN: 59604

GnomAD4 genome AF: 0.0000596 AC: 9 AN: 151044 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73654

African (AFR) AF: 0.0000244 AC: 1 AN: 41046

American (AMR) AF: 0.00 AC: 0 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.028
Sift	Benign	0.24	T
Sift4G	Benign	0.29	T
Polyphen		0.066	B
Vest4		0.32
MutPred		0.52		Loss of MoRF binding (P = 0.0122)
MVP		0.49
MPC		0.33
ClinPred		0.33	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.48
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs754826757; hg19: chr20-31954807; COSMIC: COSV59429038; COSMIC: COSV59429038;