7-92615172-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001145306.2(CDK6):c.949A>T(p.Ser317Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,022 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 18 hom. )

Consequence

CDK6
NM_001145306.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.24

Publications

7 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071578026).

BP6

Variant 7-92615172-T-A is Benign according to our data. Variant chr7-92615172-T-A is described in ClinVar as [Benign]. Clinvar id is 210641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 18 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2 link	c.949A>T	p.Ser317Cys	missense_variant	Exon 8 of 8	ENST00000424848.3	NP_001138778.1	Q00534
CDK6	NM_001259.8 link	c.949A>T	p.Ser317Cys	missense_variant	Exon 8 of 8		NP_001250.1	Q00534
CDK6	XM_047419716.1 link	c.949A>T	p.Ser317Cys	missense_variant	Exon 8 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDK6	ENST00000424848.3 link	c.949A>T	p.Ser317Cys	missense_variant	Exon 8 of 8	1	NM_001145306.2	ENSP00000397087.3	Q00534
CDK6	ENST00000265734.8 link	c.949A>T	p.Ser317Cys	missense_variant	Exon 8 of 8	1		ENSP00000265734.4	Q00534
CDK6	ENST00000467166.1 link	n.321A>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00388

AC:

969

AN:

249546

AF XY:

0.00423

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00248

AC:

3623

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1975

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33478

American (AMR)

AF:

0.00127

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00436

AC:

114

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00932

AC:

804

AN:

86238

European-Finnish (FIN)

AF:

0.0150

AC:

801

AN:

53412

Middle Eastern (MID)

AF:

0.00283

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00151

AC:

1676

AN:

1112000

Other (OTH)

AF:

0.00230

AC:

139

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

204

409

613

818

1022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00225

AC:

343

AN:

152300

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41578

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0137

AC:

146

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00184

AC:

125

AN:

68016

Other (OTH)

AF:

0.00190

AC:

AN:

2110

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

Alfa

AF:

0.00187

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00376

AC:

457

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDK6-related disorder

Benign:1

Apr 24, 2019

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). -

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

.;T

MetaRNN

Benign

0.0072

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.4

L;L

PhyloP100

2.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.041

D;D

Polyphen

0.88

P;P

Vest4

0.26

MVP

0.75

MPC

1.5

ClinPred

0.021

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.44

Mutation Taster

=99/1

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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7-92615172-T-A

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