chr7-92774737-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001145306.2(CDK6):c.328G>A(p.Asp110Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00257 in 1,610,506 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 6 hom. )

Consequence

CDK6
NM_001145306.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.10

Publications

20 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012883186).

BP6

Variant 7-92774737-C-T is Benign according to our data. Variant chr7-92774737-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434660.

BS2

High Homozygotes in GnomAdExome4 at 6 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2 link	c.328G>A	p.Asp110Asn	missense_variant	Exon 3 of 8	ENST00000424848.3	NP_001138778.1	Q00534
CDK6	NM_001259.8 link	c.328G>A	p.Asp110Asn	missense_variant	Exon 3 of 8		NP_001250.1	Q00534
CDK6	XM_047419716.1 link	c.328G>A	p.Asp110Asn	missense_variant	Exon 3 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3 link	c.328G>A	p.Asp110Asn	missense_variant	Exon 3 of 8	1	NM_001145306.2	ENSP00000397087.3		Q00534
CDK6	ENST00000265734.8 link	c.328G>A	p.Asp110Asn	missense_variant	Exon 3 of 8	1		ENSP00000265734.4		Q00534

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00287

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00147

AC:

363

AN:

247400

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.000374

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00271

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00267

AC:

3898

AN:

1458280

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

1870

AN XY:

725440

show subpopulations

African (AFR)

AF:

0.000391

AC:

AN:

33246

American (AMR)

AF:

0.00100

AC:

AN:

44020

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39422

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85428

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00330

AC:

3662

AN:

1110698

Other (OTH)

AF:

0.00257

AC:

155

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

183

366

550

733

916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152226

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41518

American (AMR)

AF:

0.000981

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00287

AC:

195

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00220

Hom.:

Bravo

AF:

0.00159

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00167

AC:

203

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDK6: BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDK6-related disorder

Benign:1

May 22, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.0077

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.13

N;N

PhyloP100

4.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.099

Sift

Benign

0.048

D;D

Sift4G

Uncertain

0.052

T;T

Polyphen

0.0

B;B

Vest4

0.14

MVP

0.65

MPC

1.1

ClinPred

0.022

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.62

Mutation Taster

=95/5

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over