NM_016408.4:c.1279G>C

Variant names:

• chr20-33370612-C-G
• rs753422405
• NM_016408.4:c.1279G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016408.4(CDK5RAP1):​c.1279G>C​(p.Asp427His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. D427N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK5RAP1 NM_016408.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP1	NM_016408.4	c.1279G>C	p.Asp427His	missense_variant	Exon 11 of 14	ENST00000346416.7	NP_057492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP1	ENST00000346416.7	c.1279G>C	p.Asp427His	missense_variant	Exon 11 of 14	1	NM_016408.4	ENSP00000217372.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	5.1	.;.;H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.0	.;D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.99
MutPred		0.94		.;.;Loss of sheet (P = 0.0357);.;
MVP		0.73
MPC		0.97
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs753422405; hg19: chr20-31958418;