12-12718165-T-G

Position:

chr12-12718165-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004064.5(CDKN1B):c.326T>G(p.Val109Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,296 control chromosomes in the GnomAD database, including 64,983 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 0.37 ( 14114 hom., cov: 33)

Exomes 𝑓: 0.25 ( 50869 hom. )

Consequence

CDKN1B
NM_004064.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.19

Variant links:

Genes affected

CDKN1B (HGNC:1785): (cyclin dependent kinase inhibitor 1B) This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

CDKN1B links:

CDKN1B (HGNC:):

CDKN1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5013622E-6).

BP6

Variant 12-12718165-T-G is Benign according to our data. Variant chr12-12718165-T-G is described in ClinVar as [Benign]. Clinvar id is 259226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-12718165-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1B	NM_004064.5 linkuse as main transcript	c.326T>G	p.Val109Gly	missense_variant	1/3	ENST00000228872.9	NP_004055.1	P46527Q6I9V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9 linkuse as main transcript	c.326T>G	p.Val109Gly	missense_variant	1/3	1	NM_004064.5	ENSP00000228872.4		P46527

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56202

AN:

152090

Hom.:

14093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.716

Gnomad AMI

AF:

0.0910

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.0451

Gnomad SAS

AF:

0.316

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.347

GnomAD3 exomes

AF:

0.259

AC:

64341

AN:

248658

Hom.:

10937

AF XY:

0.261

AC XY:

35217

AN XY:

135178

show subpopulations

Gnomad AFR exome

AF:

0.726

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.0383

Gnomad SAS exome

AF:

0.317

Gnomad FIN exome

AF:

0.253

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.247

AC:

360349

AN:

1461088

Hom.:

50869

Cov.:

AF XY:

0.248

AC XY:

180218

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.737

Gnomad4 AMR exome

AF:

0.165

Gnomad4 ASJ exome

AF:

0.251

Gnomad4 EAS exome

AF:

0.0322

Gnomad4 SAS exome

AF:

0.310

Gnomad4 FIN exome

AF:

0.250

Gnomad4 NFE exome

AF:

0.236

Gnomad4 OTH exome

AF:

0.270

GnomAD4 genome

AF:

0.370

AC:

56265

AN:

152208

Hom.:

14114

Cov.:

AF XY:

0.366

AC XY:

27242

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.716

Gnomad4 AMR

AF:

0.255

Gnomad4 ASJ

AF:

0.267

Gnomad4 EAS

AF:

0.0455

Gnomad4 SAS

AF:

0.316

Gnomad4 FIN

AF:

0.253

Gnomad4 NFE

AF:

0.240

Gnomad4 OTH

AF:

0.342

Alfa

AF:

0.253

Hom.:

9042

Bravo

AF:

0.380

TwinsUK

AF:

0.204

AC:

755

ALSPAC

AF:

0.233

AC:

899

ESP6500AA

AF:

0.693

AC:

3047

ESP6500EA

AF:

0.238

AC:

2044

ExAC

AF:

0.274

AC:

33233

Asia WGS

AF:

0.231

AC:

804

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.258

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 4

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 21177330, 24920291, 19493606, 12727815, 23624368, 27153395, 28667701, 30297969, 24532476, 25824098) -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.078

Sift

Benign

0.22

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.047

B;.

Vest4

0.13

MPC

0.089

ClinPred

0.0031

GERP RS

-0.90

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.42

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