Genetic Variant CDK6:c.648-833C>A (chr7-92623919-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.648-833C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 152,088 control chromosomes in the GnomAD database, including 184 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 0.044 ( 184 hom., cov: 32)

Consequence

CDK6
NM_001145306.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.24

Publications

10 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=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CDK6	NM_001145306.2 link	c.648-833C>A	intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8 link	c.648-833C>A	intron_variant	Intron 5 of 7		NP_001250.1
CDK6	XM_047419716.1 link	c.648-833C>A	intron_variant	Intron 5 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3 link	c.648-833C>A		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8 link	c.648-833C>A		intron_variant	Intron 5 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes

AF:

0.0442

AC:

6712

AN:

151970

Hom.:

185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0353

Gnomad ASJ

AF:

0.0844

Gnomad EAS

AF:

0.00637

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.0446

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0583

Gnomad OTH

AF:

0.0417

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

GnomAD4 genome

AF:

0.0442

AC:

6717

AN:

152088

Hom.:

184

Cov.:

AF XY:

0.0433

AC XY:

3218

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0271

AC:

1124

AN:

41486

American (AMR)

AF:

0.0352

AC:

538

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0844

AC:

293

AN:

3470

East Asian (EAS)

AF:

0.00638

AC:

AN:

5172

South Asian (SAS)

AF:

0.0350

AC:

169

AN:

4826

European-Finnish (FIN)

AF:

0.0446

AC:

471

AN:

10570

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0583

AC:

3964

AN:

67986

Other (OTH)

AF:

0.0417

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

322

643

965

1286

1608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0557

Hom.:

414

Bravo

AF:

0.0426

Asia WGS

AF:

0.0290

AC:

103

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.1

(source)

DANN

Benign

0.42

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(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