rs1407809457

Variant names:

• chr20-33385738-C-T
• rs1407809457
• NM_016408.4:c.788G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016408.4(CDK5RAP1):​c.788G>A​(p.Ser263Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDK5RAP1 NM_016408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

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.788G>A	p.Ser263Asn	missense	Exon 7 of 14	NP_057492.2
	CDK5RAP1	NM_001365728.1		c.788G>A	p.Ser263Asn	missense	Exon 7 of 15	NP_001352657.1	Q96SZ6-1
	CDK5RAP1	NM_016082.4		c.791G>A	p.Ser264Asn	missense	Exon 7 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.788G>A	p.Ser263Asn	missense	Exon 7 of 14	ENSP00000217372.2	Q96SZ6-3
	CDK5RAP1	ENST00000339269.5	TSL:1	c.788G>A	p.Ser263Asn	missense	Exon 7 of 13	ENSP00000341840.5	Q96SZ6-4
	CDK5RAP1	ENST00000874266.1		c.788G>A	p.Ser263Asn	missense	Exon 7 of 15	ENSP00000544325.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461512 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		1.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.29
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.75
MutPred		0.75		Gain of sheet (P = 0.039)
MVP		0.62
MPC		0.79
ClinPred		0.94	D
GERP RS		2.6
Varity_R		0.33
gMVP		0.89
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1407809457; hg19: chr20-31973544;