12-55972376-G-C

Position:

• chr12-55972376-G-C

Variant summary

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

The NM_001798.5(CDK2):​c.*751G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,064 control chromosomes in the GnomAD database, including 2,367 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 0.14 (2367 hom., cov: 31)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: CDK2 NM_001798.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317

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=-0.71).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK2	NM_001798.5	c.*751G>C		3_prime_UTR_variant	7/7	ENST00000266970.9	NP_001789.2
CDK2	NM_001290230.2	c.*751G>C		3_prime_UTR_variant	5/5		NP_001277159.1
CDK2	NM_052827.4	c.*751G>C		3_prime_UTR_variant	6/6		NP_439892.2
CDK2	XM_011537732.2	c.*751G>C		3_prime_UTR_variant	8/8		XP_011536034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK2	ENST00000266970.9	c.*751G>C		3_prime_UTR_variant	7/7	1	NM_001798.5	ENSP00000266970	P1
PMEL	ENST00000549233.2	c.-95-609C>G		intron_variant		5		ENSP00000448871
CDK2	ENST00000555408.5	c.*2260G>C		3_prime_UTR_variant, NMD_transcript_variant	6/6	3		ENSP00000450983

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21662 AN: 151934 Hom.: 2357 Cov.: 31

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0714 AC: 1 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 1 AN XY: 12

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.143 AC: 21704 AN: 152050 Hom.: 2367 Cov.: 31 AF XY: 0.139 AC XY: 10316 AN XY: 74340

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.0930

Gnomad4 ASJ AF: 0.0853

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.0546

Gnomad4 FIN AF: 0.0757

Gnomad4 NFE AF: 0.0842

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0521 Hom.: 61

Bravo AF: 0.152

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.1
DANN	Benign	0.86
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: rs1045435; hg19: chr12-56366160;