20-33372648-T-C

Variant names:

• chr20-33372648-T-C
• rs200680704
• NM_016408.4:c.1255A>G

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.1255A>G​(p.Ile419Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,530,796 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CDK5RAP1 NM_016408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43
• 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=0.11193639).

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.1255A>G	p.Ile419Val	missense	Exon 10 of 14	NP_057492.2
	CDK5RAP1	NM_001365728.1		c.1297A>G	p.Ile433Val	missense	Exon 11 of 15	NP_001352657.1	Q96SZ6-1
	CDK5RAP1	NM_016082.4		c.1258A>G	p.Ile420Val	missense	Exon 10 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.1255A>G	p.Ile419Val	missense	Exon 10 of 14	ENSP00000217372.2	Q96SZ6-3
	CDK5RAP1	ENST00000339269.5	TSL:1	c.1024A>G	p.Ile342Val	missense	Exon 9 of 13	ENSP00000341840.5	Q96SZ6-4
	CDK5RAP1	ENST00000874266.1		c.1348A>G	p.Ile450Val	missense	Exon 11 of 15	ENSP00000544325.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000103 AC: 2 AN: 193286 AF XY: 0.00000943

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378456 Hom.: 0 Cov.: 24 AF XY: 0.00000146 AC XY: 1 AN XY: 686302

African (AFR) AF: 0.00 AC: 0 AN: 28988

American (AMR) AF: 0.00 AC: 0 AN: 28870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23292

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36742

South Asian (SAS) AF: 0.00 AC: 0 AN: 74386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072766

Other (OTH) AF: 0.00 AC: 0 AN: 56790

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74508

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

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	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.057
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.032	B
Vest4		0.32
MVP		0.20
MPC		0.25
ClinPred		0.29	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.41
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200680704; hg19: chr20-31960454;