2-218959933-G-T

Variant names:

• chr2-218959933-G-T
• rs1945189360
• NM_003936.5:c.113G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003936.5(CDK5R2):​c.113G>T​(p.Gly38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 1,512,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. G38D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CDK5R2 NM_003936.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34482723).

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.113G>T	p.Gly38Val	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.113G>T	p.Gly38Val	missense	Exon 1 of 1	ENSP00000304250.4	Q13319
	CDK5R2-AS1	ENST00000429343.1	TSL:4	n.45+1926C>A		intron	N/A
	CDK5R2-AS1	ENST00000798770.1		n.277+1926C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360374 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 669746

African (AFR) AF: 0.00 AC: 0 AN: 28602

American (AMR) AF: 0.00 AC: 0 AN: 30470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24148

East Asian (EAS) AF: 0.00 AC: 0 AN: 33710

South Asian (SAS) AF: 0.00 AC: 0 AN: 75716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4408

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1065914

Other (OTH) AF: 0.00 AC: 0 AN: 56392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Benign	0.034	D
Sift4G	Benign	0.15	T
Polyphen		0.91	P
Vest4		0.12
MutPred		0.39		Gain of sheet (P = 0.0166)
MVP		0.75
ClinPred		0.70	D
GERP RS		4.1
PromoterAI		-0.019	Neutral
Varity_R		0.20
gMVP		0.57
Mutation Taster		=96/4	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: rs1945189360; hg19: chr2-219824655;