7-92615172-T-A

Position:

chr7-92615172-T-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_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. 15/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CDK6. . Gene score misZ 3.0596 (greater than the threshold 3.09). Trascript score misZ 3.1324 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive primary microcephaly, microcephaly 12, primary, autosomal recessive.

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 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDK6	NM_001145306.2 linkuse as main transcript	c.949A>T	p.Ser317Cys	missense_variant	8/8	ENST00000424848.3
CDK6	NM_001259.8 linkuse as main transcript	c.949A>T	p.Ser317Cys	missense_variant	8/8
CDK6	XM_047419716.1 linkuse as main transcript	c.949A>T	p.Ser317Cys	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CDK6	ENST00000424848.3 linkuse as main transcript	c.949A>T	p.Ser317Cys	missense_variant	8/8	1	NM_001145306.2	P1
CDK6	ENST00000265734.8 linkuse as main transcript	c.949A>T	p.Ser317Cys	missense_variant	8/8	1		P1
CDK6	ENST00000467166.1 linkuse as main transcript	n.321A>T		non_coding_transcript_exon_variant	2/2	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

GnomAD3 exomes

AF:

0.00388

AC:

969

AN:

249546

Hom.:

AF XY:

0.00423

AC XY:

571

AN XY:

135038

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 SAS exome

AF:

0.0106

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

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00436

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00932

Gnomad4 FIN exome

AF:

0.0150

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00225

AC:

343

AN:

152300

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00622

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.00190

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

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 10, 2015

- -

CDK6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

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

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

MutationTaster

Benign

0.56

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over