12-55972376-G-C

Variant names:

• chr12-55972376-G-C
• rs1045435
• NM_001798.5:c.*751G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CDK2	NM_001798.5	c.*751G>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000266970.9	NP_001789.2
CDK2	NM_052827.4	c.*751G>C		3_prime_UTR_variant	Exon 6 of 6		NP_439892.2
CDK2	NM_001290230.2	c.*751G>C		3_prime_UTR_variant	Exon 5 of 5		NP_001277159.1
CDK2	XM_011537732.2	c.*751G>C		3_prime_UTR_variant	Exon 8 of 8		XP_011536034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK2	ENST00000266970.9	c.*751G>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_001798.5	ENSP00000266970.4
CDK2	ENST00000555408.5	n.*2260G>C		non_coding_transcript_exon_variant	Exon 6 of 6	3		ENSP00000450983.1
CDK2	ENST00000555408.5	n.*2260G>C		3_prime_UTR_variant	Exon 6 of 6	3		ENSP00000450983.1
PMEL	ENST00000549233.2	c.-95-609C>G		intron_variant	Intron 1 of 5	5		ENSP00000448871.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.100 AC: 1 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.309 AC: 12784 AN: 41412

American (AMR) AF: 0.0930 AC: 1421 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 296 AN: 3470

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5178

South Asian (SAS) AF: 0.0546 AC: 263 AN: 4818

European-Finnish (FIN) AF: 0.0757 AC: 802 AN: 10594

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0842 AC: 5726 AN: 67984

Other (OTH) AF: 0.110 AC: 232 AN: 2112

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
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1045435; hg19: chr12-56366160;