Genetic Variant CDK6:c.370-19845C>A (chr7-92745638-G-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.370-19845C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 152,204 control chromosomes in the GnomAD database, including 300 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 0.028 ( 300 hom., cov: 32)

Consequence

CDK6
NM_001145306.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.463

Publications

1 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=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2 link	c.370-19845C>A	intron_variant	Intron 3 of 7	ENST00000424848.3	NP_001138778.1	Q00534
CDK6	NM_001259.8 link	c.370-19845C>A	intron_variant	Intron 3 of 7		NP_001250.1	Q00534
CDK6	XM_047419716.1 link	c.370-19845C>A	intron_variant	Intron 3 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3 link	c.370-19845C>A		intron_variant	Intron 3 of 7	1	NM_001145306.2	ENSP00000397087.3		Q00534
CDK6	ENST00000265734.8 link	c.370-19845C>A		intron_variant	Intron 3 of 7	1		ENSP00000265734.4		Q00534

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4327

AN:

152086

Hom.:

301

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.311

Gnomad SAS

AF:

0.0785

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.0373

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0285

AC:

4336

AN:

152204

Hom.:

300

Cov.:

AF XY:

0.0314

AC XY:

2338

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0168

AC:

696

AN:

41542

American (AMR)

AF:

0.0252

AC:

385

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3472

East Asian (EAS)

AF:

0.310

AC:

1601

AN:

5166

South Asian (SAS)

AF:

0.0780

AC:

376

AN:

4822

European-Finnish (FIN)

AF:

0.0211

AC:

223

AN:

10592

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

832

AN:

68014

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

193

386

580

773

966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0207

Hom.:

351

Bravo

AF:

0.0288

Asia WGS

AF:

0.168

AC:

582

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

4.4

(source)

DANN

Benign

0.63

PhyloP100

-0.46

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over