12-57747819-C-T

Position:

• chr12-57747819-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000075.4(CDK4):​c.*706G>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 0.212 in 168,038 control chromosomes in the GnomAD database, including 4,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3958 hom., cov: 31)
  • Exomes 𝑓: 0.15 (243 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.323

Genes affected

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-57747819-C-T is Benign according to our data. Variant chr12-57747819-C-T is described in ClinVar as [Benign]. Clinvar id is 309965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*706G>A		3_prime_UTR_variant	8/8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*529C>T		3_prime_UTR_variant	6/6	ENST00000257910.8	NP_005972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.*706G>A		3_prime_UTR_variant	8/8	1	NM_000075.4	ENSP00000257904	P1
TSPAN31	ENST00000257910.8	c.*529C>T		3_prime_UTR_variant	6/6	1	NM_005981.5	ENSP00000257910	P1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33185 AN: 151684 Hom.: 3953 Cov.: 31

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.149 AC: 2413 AN: 16238 Hom.: 243 Cov.: 0 AF XY: 0.147 AC XY: 1148 AN XY: 7802

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.0874

Gnomad4 EAS exome AF: 0.0818

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.219 AC: 33207 AN: 151800 Hom.: 3958 Cov.: 31 AF XY: 0.215 AC XY: 15979 AN XY: 74172

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.198

Alfa AF: 0.207 Hom.: 431

Bravo AF: 0.235

Asia WGS AF: 0.112 AC: 390 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.64

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: rs184712; hg19: chr12-58141602;