Genetic Variant CDK6:c.648-5854T>A (chr7-92628940-A-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001145306.2(CDK6):c.648-5854T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0868 in 152,150 control chromosomes in the GnomAD database, including 755 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 0.087 ( 755 hom., cov: 32)

Consequence

CDK6
NM_001145306.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2 link	c.648-5854T>A	intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1	Q00534
CDK6	NM_001259.8 link	c.648-5854T>A	intron_variant	Intron 5 of 7		NP_001250.1	Q00534
CDK6	XM_047419716.1 link	c.648-5854T>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.648-5854T>A		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3		Q00534
CDK6	ENST00000265734.8 link	c.648-5854T>A		intron_variant	Intron 5 of 7	1		ENSP00000265734.4		Q00534

Frequencies

GnomAD3 genomes

AF:

0.0868

AC:

13201

AN:

152032

Hom.:

754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0203

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.0747

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0776

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

GnomAD4 genome

AF:

0.0868

AC:

13211

AN:

152150

Hom.:

755

Cov.:

AF XY:

0.0898

AC XY:

6684

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0203

AC:

842

AN:

41556

American (AMR)

AF:

0.177

AC:

2706

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3472

East Asian (EAS)

AF:

0.0749

AC:

387

AN:

5166

South Asian (SAS)

AF:

0.117

AC:

566

AN:

4822

European-Finnish (FIN)

AF:

0.128

AC:

1358

AN:

10592

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7053

AN:

67966

Other (OTH)

AF:

0.0773

AC:

163

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

599

1197

1796

2394

2993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.0959

Hom.:

106

Bravo

AF:

0.0864

Asia WGS

AF:

0.102

AC:

355

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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