rs2069408

Positions:

• chr12-55970537-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001798.5(CDK2):​c.589-507A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 682,372 control chromosomes in the GnomAD database, including 28,343 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (5201 hom., cov: 31)
  • Exomes 𝑓: 0.29 (23142 hom.)
• Consequence: CDK2 NM_001798.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

Genes affected

CDK2 (HGNC:1771): (cyclin dependent kinase 2) This gene encodes a member of a family of serine/threonine protein kinases that participate in cell cycle regulation. The encoded protein is the catalytic subunit of the cyclin-dependent protein kinase complex, which regulates progression through the cell cycle. Activity of this protein is especially critical during the G1 to S phase transition. This protein associates with and regulated by other subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A), and p27Kip1 (CDKN1B). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK2	NM_001798.5	c.589-507A>G		intron_variant		ENST00000266970.9	NP_001789.2
CDK2	NM_001290230.2	c.409-507A>G		intron_variant			NP_001277159.1
CDK2	NM_052827.4	c.487-507A>G		intron_variant			NP_439892.2
CDK2	XM_011537732.2	c.589-61A>G		intron_variant			XP_011536034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK2	ENST00000266970.9	c.589-507A>G		intron_variant		1	NM_001798.5	ENSP00000266970	P1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36876 AN: 151950 Hom.: 5201 Cov.: 31

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.263

GnomAD4 exome AF: 0.286 AC: 151805 AN: 530304 Hom.: 23142 AF XY: 0.283 AC XY: 80800 AN XY: 285754

Gnomad4 AFR exome AF: 0.0938

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.312

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.242 AC: 36873 AN: 152068 Hom.: 5201 Cov.: 31 AF XY: 0.240 AC XY: 17827 AN XY: 74334

Gnomad4 AFR AF: 0.0976

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.260

Alfa AF: 0.309 Hom.: 17121

Bravo AF: 0.235

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.57

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: rs2069408; hg19: chr12-56364321; COSMIC: COSV57185787; COSMIC: COSV57185787;