12-57748315-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000075.4(CDK4):c.*210G>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 0.0028 in 588,326 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (1 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.168

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-57748315-C-T is Benign according to our data. Variant chr12-57748315-C-T is described in ClinVar as [Benign]. Clinvar id is 309977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK4	NM_000075.4	c.*210G>A		3_prime_UTR_variant	8/8	ENST00000257904.11
TSPAN31	NM_005981.5	c.*1025C>T		3_prime_UTR_variant	6/6	ENST00000257910.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK4	ENST00000257904.11	c.*210G>A		3_prime_UTR_variant	8/8	1	NM_000075.4	P1
TSPAN31	ENST00000257910.8	c.*1025C>T		3_prime_UTR_variant	6/6	1	NM_005981.5	P1
CDK4	ENST00000312990.10	c.*434G>A		3_prime_UTR_variant	7/7	1
TSPAN31	ENST00000547992.5	c.*1025C>T		3_prime_UTR_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 407 AN: 151188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000706

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00599

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00193

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00671

GnomAD4 exome AF: 0.00284 AC: 1241 AN: 437028 Hom.: 1 Cov.: 0 AF XY: 0.00262 AC XY: 618 AN XY: 235854

Gnomad4 AFR exome AF: 0.000941

Gnomad4 AMR exome AF: 0.00555

Gnomad4 ASJ exome AF: 0.00307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000253

Gnomad4 FIN exome AF: 0.000858

Gnomad4 NFE exome AF: 0.00366

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00269 AC: 407 AN: 151298 Hom.: 0 Cov.: 32 AF XY: 0.00261 AC XY: 193 AN XY: 73852

Gnomad4 AFR AF: 0.000704

Gnomad4 AMR AF: 0.00599

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00193

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	3.2
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2069511; hg19: chr12-58142098;