Genetic Variant CDK4:c.*302_*303dupTT (chr12-57748221-T-TAA) – 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.*302_*303dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 324,872 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 0 hom. )

Consequence

CDK4
NM_000075.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.557

Publications

2 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 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000075.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDK4	NM_000075.4	MANE Select	c.302_303dupTT	3_prime_UTR	Exon 8 of 8	NP_000066.1	P11802-1
TSPAN31	NM_005981.5	MANE Select	c.944_945dupAA	3_prime_UTR	Exon 6 of 6	NP_005972.1	Q12999
TSPAN31	NM_001330169.2		c.944_945dupAA	3_prime_UTR	Exon 6 of 6	NP_001317098.1	B4DFJ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDK4	ENST00000257904.11	TSL:1 MANE Select	c.302_303dupTT	3_prime_UTR	Exon 8 of 8	ENSP00000257904.5	P11802-1
TSPAN31	ENST00000257910.8	TSL:1 MANE Select	c.944_945dupAA	3_prime_UTR	Exon 6 of 6	ENSP00000257910.3	Q12999
TSPAN31	ENST00000547992.5	TSL:1	c.944_945dupAA	3_prime_UTR	Exon 4 of 4	ENSP00000448209.1	F8VS78

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

137152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000730

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00184

AC:

345

AN:

187684

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

181

AN XY:

96472

show subpopulations

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

African (AFR)

AF:

0.00465

AC:

AN:

6666

American (AMR)

AF:

0.00107

AC:

AN:

6554

Ashkenazi Jewish (ASJ)

AF:

0.00266

AC:

AN:

7152

East Asian (EAS)

AF:

0.000976

AC:

AN:

15364

South Asian (SAS)

AF:

0.00239

AC:

AN:

22176

European-Finnish (FIN)

AF:

0.00203

AC:

AN:

5422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

816

European-Non Finnish (NFE)

AF:

0.00171

AC:

192

AN:

112032

Other (OTH)

AF:

0.00148

AC:

AN:

11502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

137188

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

66256

show subpopulations

African (AFR)

AF:

0.000475

AC:

AN:

37908

American (AMR)

AF:

0.0000729

AC:

AN:

13720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3218

East Asian (EAS)

AF:

0.00

AC:

AN:

4810

South Asian (SAS)

AF:

0.00

AC:

AN:

4322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62546

Other (OTH)

AF:

0.00

AC:

AN:

1850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.56

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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12-57748221-TAAAAA-TAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over