Genetic Variant CDK6:c.*735G>A (chr7-92614405-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001145306.2(CDK6):c.*735G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 232,660 control chromosomes in the GnomAD database, including 10,883 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7464 hom., cov: 32)

Exomes 𝑓: 0.27 ( 3419 hom. )

Consequence

CDK6
NM_001145306.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.958

Publications

19 publications found

Variant links:

Genes affected

CDK6 (HGNC:1777): (cyclin dependent kinase 6) The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. Altered expression of this gene has been observed in multiple human cancers. A mutation in this gene resulting in reduced cell proliferation, and impaired cell motility and polarity, and has been identified in patients with primary microcephaly. [provided by RefSeq, Aug 2017]

CDK6 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microcephaly 12, primary, autosomal recessive
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CDK6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2 link	c.*735G>A	3_prime_UTR_variant	Exon 8 of 8	ENST00000424848.3	NP_001138778.1	Q00534
CDK6	NM_001259.8 link	c.*735G>A	3_prime_UTR_variant	Exon 8 of 8		NP_001250.1	Q00534
CDK6	XM_047419716.1 link	c.*735G>A	3_prime_UTR_variant	Exon 8 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3 link	c.*735G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_001145306.2	ENSP00000397087.3		Q00534
CDK6	ENST00000265734.8 link	c.*735G>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000265734.4		Q00534

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

45954

AN:

151842

Hom.:

7456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.372

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.371

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.311

Gnomad OTH

AF:

0.302

GnomAD4 exome

AF:

0.269

AC:

21695

AN:

80700

Hom.:

3419

Cov.:

AF XY:

0.271

AC XY:

10030

AN XY:

37066

show subpopulations

African (AFR)

AF:

0.381

AC:

1478

AN:

3882

American (AMR)

AF:

0.232

AC:

580

AN:

2496

Ashkenazi Jewish (ASJ)

AF:

0.372

AC:

1899

AN:

5110

East Asian (EAS)

AF:

0.0162

AC:

184

AN:

11342

South Asian (SAS)

AF:

0.144

AC:

101

AN:

700

European-Finnish (FIN)

AF:

0.310

AC:

AN:

Middle Eastern (MID)

AF:

0.302

AC:

148

AN:

490

European-Non Finnish (NFE)

AF:

0.306

AC:

15252

AN:

49878

Other (OTH)

AF:

0.302

AC:

2035

AN:

6744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

690

1379

2069

2758

3448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.303

AC:

46004

AN:

151960

Hom.:

7464

Cov.:

AF XY:

0.297

AC XY:

22094

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.373

AC:

15438

AN:

41412

American (AMR)

AF:

0.228

AC:

3489

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.371

AC:

1287

AN:

3470

East Asian (EAS)

AF:

0.0211

AC:

109

AN:

5178

South Asian (SAS)

AF:

0.138

AC:

666

AN:

4824

European-Finnish (FIN)

AF:

0.269

AC:

2839

AN:

10544

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.311

AC:

21122

AN:

67932

Other (OTH)

AF:

0.300

AC:

633

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1602

3204

4807

6409

8011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.308

Hom.:

11720

Bravo

AF:

0.305

Asia WGS

AF:

0.130

AC:

454

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.44

(source)

DANN

Benign

0.63

PhyloP100

-0.96

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over