12-57747747-C-CT

Variant names:

• chr12-57747747-C-CT
• rs146863045
• NM_000075.4:c.*777dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000075.4(CDK4):​c.*777dupA 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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 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 GnomAdExome4. There are 108 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position FAILED quality control check. 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 rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*777dupA		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*470dupT		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904	c.*777dupA		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*470dupT		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

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 AC: 1 AN: 78

Gnomad4 AMR exome AF: 0.0558 AC: 22 AN: 394

Gnomad4 ASJ exome AF: 0.0333 AC: 8 AN: 240

Gnomad4 EAS exome AF: 0.0335 AC: 21 AN: 626

Gnomad4 SAS exome AF: 0.0427 AC: 10 AN: 234

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 16

Gnomad4 NFE exome AF: 0.0427 AC: 128 AN: 2998

Gnomad4 Remaining exome AF: 0.0414 AC: 11 AN: 266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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 AC: 0.00206921 AN: 0.00206921

Gnomad4 AMR AF: 0.00845 AC: 0.00845378 AN: 0.00845378

Gnomad4 ASJ AF: 0.00118 AC: 0.00118064 AN: 0.00118064

Gnomad4 EAS AF: 0.00198 AC: 0.00198098 AN: 0.00198098

Gnomad4 SAS AF: 0.00803 AC: 0.00802603 AN: 0.00802603

Gnomad4 FIN AF: 0.00184 AC: 0.00184422 AN: 0.00184422

Gnomad4 NFE AF: 0.00739 AC: 0.00738805 AN: 0.00738805

Gnomad4 OTH AF: 0.0101 AC: 0.0100705 AN: 0.0100705

Alfa AF: 0.000515 Hom.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cutaneous Malignant Melanoma, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism

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;