12-57747747-C-CT

Position:

• chr12-57747747-C-CT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000075.4(CDK4):​c.*777_*778insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 151,274 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 31)
  • Exomes 𝑓: 0.041 (0 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.674

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0414 (202/4878) while in subpopulation AMR AF= 0.0558 (22/394). AF 95% confidence interval is 0.0378. There are 0 homozygotes in gnomad4_exome. There are 108 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 786 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*777_*778insA		3_prime_UTR_variant	8/8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*470dup		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.*777_*778insA		3_prime_UTR_variant	8/8	1	NM_000075.4	ENSP00000257904	P1
TSPAN31	ENST00000257910.8	c.*470dup		3_prime_UTR_variant	6/6	1	NM_005981.5	ENSP00000257910	P1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 782 AN: 146346 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00846

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00198

Gnomad SAS AF: 0.00822

Gnomad FIN AF: 0.00184

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00740

Gnomad OTH AF: 0.00761

GnomAD4 exome AF: 0.0414 AC: 202 AN: 4878 Hom.: 0 Cov.: 0 AF XY: 0.0454 AC XY: 108 AN XY: 2378

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.0558

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.0335

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0427

Gnomad4 OTH exome AF: 0.0414

GnomAD4 genome AF: 0.00537 AC: 786 AN: 146396 Hom.: 4 Cov.: 31 AF XY: 0.00491 AC XY: 350 AN XY: 71298

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00845

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.00198

Gnomad4 SAS AF: 0.00803

Gnomad4 FIN AF: 0.00184

Gnomad4 NFE AF: 0.00739

Gnomad4 OTH AF: 0.0101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cutaneous Malignant Melanoma, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs146863045; hg19: chr12-58141530;