Genetic Variant NM_001145306.2:c.234-4184G>A (chr7-92779015-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.234-4184G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 149,438 control chromosomes in the GnomAD database, including 1,989 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 0.14 ( 1989 hom., cov: 30)

Consequence

CDK6
NM_001145306.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.613

Publications

0 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=-0.8).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CDK6	NM_001145306.2 link	c.234-4184G>A	intron_variant	Intron 2 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8 link	c.234-4184G>A	intron_variant	Intron 2 of 7		NP_001250.1
CDK6	XM_047419716.1 link	c.234-4184G>A	intron_variant	Intron 2 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3 link	c.234-4184G>A		intron_variant	Intron 2 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8 link	c.234-4184G>A		intron_variant	Intron 2 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20453

AN:

149332

Hom.:

1989

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0361

Gnomad AMI

AF:

0.419

Gnomad AMR

AF:

0.0886

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.00137

Gnomad SAS

AF:

0.0360

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.0714

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.132

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

GnomAD4 genome

AF:

0.137

AC:

20448

AN:

149438

Hom.:

1989

Cov.:

AF XY:

0.132

AC XY:

9657

AN XY:

72904

show subpopulations

African (AFR)

AF:

0.0359

AC:

1452

AN:

40416

American (AMR)

AF:

0.0882

AC:

1326

AN:

15028

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

501

AN:

3454

East Asian (EAS)

AF:

0.00137

AC:

AN:

5106

South Asian (SAS)

AF:

0.0358

AC:

167

AN:

4664

European-Finnish (FIN)

AF:

0.226

AC:

2239

AN:

9902

Middle Eastern (MID)

AF:

0.0764

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.208

AC:

14083

AN:

67604

Other (OTH)

AF:

0.131

AC:

271

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

783

1566

2348

3131

3914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.177

Hom.:

1431

Bravo

AF:

0.121

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.7

(source)

DANN

Benign

0.71

PhyloP100

-0.61

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