rs2069414

Positions:

• chr12-55971915-C-A
• chr12-55971915-C-T

Variant summary

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

The NM_001798.5(CDK2):​c.*290C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 345,882 control chromosomes in the GnomAD database, including 504 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 0.041 (185 hom., cov: 32)
  • Exomes 𝑓: 0.053 (319 hom.)
• Consequence: CDK2 NM_001798.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85

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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK2	NM_001798.5	c.*290C>A		3_prime_UTR_variant	7/7	ENST00000266970.9
CDK2	NM_001290230.2	c.*290C>A		3_prime_UTR_variant	5/5
CDK2	NM_052827.4	c.*290C>A		3_prime_UTR_variant	6/6
CDK2	XM_011537732.2	c.*290C>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK2	ENST00000266970.9	c.*290C>A		3_prime_UTR_variant	7/7	1	NM_001798.5	P1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6168 AN: 152088 Hom.: 185 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.0374

GnomAD4 exome AF: 0.0526 AC: 10195 AN: 193676 Hom.: 319 Cov.: 0 AF XY: 0.0526 AC XY: 5235 AN XY: 99556

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.0251

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.000143

Gnomad4 SAS exome AF: 0.0371

Gnomad4 FIN exome AF: 0.0550

Gnomad4 NFE exome AF: 0.0660

Gnomad4 OTH exome AF: 0.0461

GnomAD4 genome AF: 0.0405 AC: 6170 AN: 152206 Hom.: 185 Cov.: 32 AF XY: 0.0396 AC XY: 2945 AN XY: 74408

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0353

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.0646

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0531 Hom.: 337

Bravo AF: 0.0377

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.20
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs2069414; hg19: chr12-56365699;