chr12-57747747-C-CT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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
• Publications: 0 publications found

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 -4 ACMG points.

• 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	ENST00000257904.11	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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0128 AC: 1 AN: 78

American (AMR) AF: 0.0558 AC: 22 AN: 394

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 8 AN: 240

East Asian (EAS) AF: 0.0335 AC: 21 AN: 626

South Asian (SAS) AF: 0.0427 AC: 10 AN: 234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16

Middle Eastern (MID) AF: 0.0385 AC: 1 AN: 26

European-Non Finnish (NFE) AF: 0.0427 AC: 128 AN: 2998

Other (OTH) AF: 0.0414 AC: 11 AN: 266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), 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

African (AFR) AF: 0.00207 AC: 83 AN: 40112

American (AMR) AF: 0.00845 AC: 124 AN: 14668

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3388

East Asian (EAS) AF: 0.00198 AC: 10 AN: 5048

South Asian (SAS) AF: 0.00803 AC: 37 AN: 4610

European-Finnish (FIN) AF: 0.00184 AC: 17 AN: 9218

Middle Eastern (MID) AF: 0.00714 AC: 2 AN: 280

European-Non Finnish (NFE) AF: 0.00739 AC: 489 AN: 66188

Other (OTH) AF: 0.0101 AC: 20 AN: 1986

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
PhyloP100		-0.67
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

Other links and lift over

dbSNP: rs146863045; hg19: chr12-58141530;