2-218960296-C-T

Variant names:

• chr2-218960296-C-T
• rs1442704952
• NM_003936.5:c.476C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003936.5(CDK5R2):​c.476C>T​(p.Pro159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000409 in 1,222,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDK5R2 NM_003936.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

Genes affected

CDK5R2 (HGNC:1776): (cyclin dependent kinase 5 regulatory subunit 2) The protein encoded by this gene is a neuron-specific activator of CDK5 kinase. It associates with CDK5 to form an active kinase. This protein and neuron-specific CDK5 activator CDK5R1/p39NCK5A both share limited similarity to cyclins, and thus may define a distinct family of cyclin-dependent kinase activating proteins. [provided by RefSeq, Jul 2008]

CDK5R2-AS1 (HGNC:55677): (CDK5R2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21997768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5R2	NM_003936.5	c.476C>T	p.Pro159Leu	missense_variant	Exon 1 of 1	ENST00000302625.6	NP_003927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5R2	ENST00000302625.6	c.476C>T	p.Pro159Leu	missense_variant	Exon 1 of 1	6	NM_003936.5	ENSP00000304250.4
CDK5R2-AS1	ENST00000429343.1	n.45+1563G>A		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000409 AC: 5 AN: 1222598 Hom.: 0 Cov.: 31 AF XY: 0.00000502 AC XY: 3 AN XY: 597352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000147

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.95e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476C>T (p.P159L) alteration is located in exon 1 (coding exon 1) of the CDK5R2 gene. This alteration results from a C to T substitution at nucleotide position 476, causing the proline (P) at amino acid position 159 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.13
Sift	Benign	0.23	T
Sift4G	Benign	0.45	T
Polyphen		0.77	P
Vest4		0.25
MutPred		0.41		Loss of glycosylation at P159 (P = 3e-04);
MVP		0.64
ClinPred		0.27	T
GERP RS		2.0
Varity_R		0.069
gMVP		0.32

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: rs1442704952; hg19: chr2-219825018;