Genetic Variant CDK4:c.*762_*763delGT (chr12-57747761-GAC-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000075.4(CDK4):c.*762_*763delGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 143,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDK4
NM_000075.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0620

Publications

1 publications found

Variant links:

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]

CDK4 links:

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]

TSPAN31 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4 link	c.762_763delGT		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1	P11802-1A0A024RBB6
TSPAN31	NM_005981.5 link	c.475_476delCA		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1	Q12999

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11 link	c.762_763delGT		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5		P11802-1
TSPAN31	ENST00000257910.8 link	c.475_476delCA		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3		Q12999

Frequencies

GnomAD3 genomes

AF:

0.0000974

AC:

AN:

143782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000137

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

7346

Hom.:

AF XY:

0.00

AC XY:

AN XY:

3590

African (AFR)

AF:

0.00

AC:

AN:

118

American (AMR)

AF:

0.00

AC:

AN:

624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

334

East Asian (EAS)

AF:

0.00

AC:

AN:

930

South Asian (SAS)

AF:

0.00

AC:

AN:

362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

4500

Other (OTH)

AF:

0.00

AC:

AN:

428

GnomAD4 genome

AF:

0.0000974

AC:

AN:

143782

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

69666

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

38880

American (AMR)

AF:

0.00

AC:

AN:

14514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

4936

South Asian (SAS)

AF:

0.00

AC:

AN:

4570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000137

AC:

AN:

65522

Other (OTH)

AF:

0.00

AC:

AN:

1980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

-0.062

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr12-57747761-GAC-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over