2-218960217-G-T

Variant names:

• chr2-218960217-G-T
• rs908098030
• NM_003936.5:c.397G>T

Variant summary

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

The NM_003936.5(CDK5R2):​c.397G>T​(p.Ala133Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000801 in 1,248,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. A133T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: CDK5R2 NM_003936.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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

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=0.16588256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003936.5. 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
	CDK5R2	NM_003936.5	MANE Select	c.397G>T	p.Ala133Ser	missense	Exon 1 of 1	NP_003927.1	Q13319

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5R2	ENST00000302625.6	TSL:6 MANE Select	c.397G>T	p.Ala133Ser	missense	Exon 1 of 1	ENSP00000304250.4	Q13319
	CDK5R2-AS1	ENST00000429343.1	TSL:4	n.45+1642C>A		intron	N/A
	CDK5R2-AS1	ENST00000798770.1		n.277+1642C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.01e-7 AC: 1 AN: 1248612 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 611690

African (AFR) AF: 0.00 AC: 0 AN: 24394

American (AMR) AF: 0.00 AC: 0 AN: 14114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21076

East Asian (EAS) AF: 0.00 AC: 0 AN: 27410

South Asian (SAS) AF: 0.00 AC: 0 AN: 57530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4152

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1013668

Other (OTH) AF: 0.00 AC: 0 AN: 50910

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.57	N
REVEL	Benign	0.12
Sift	Benign	0.73	T
Sift4G	Benign	1.0	T
Polyphen		0.39	B
Vest4		0.092
MutPred		0.35		Gain of glycosylation at A133 (P = 0.0031)
MVP		0.67
ClinPred		0.59	D
GERP RS		3.6
Varity_R		0.098
gMVP		0.20
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs908098030; hg19: chr2-219824939;