12-12718195-T-C

Position:

chr12-12718195-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004064.5(CDKN1B):c.356T>C(p.Ile119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,613,028 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00061 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 2 hom. )

Consequence

CDKN1B
NM_004064.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 0.482

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01424861).

BP6

Variant 12-12718195-T-C is Benign according to our data. Variant chr12-12718195-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 307664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=1}. Variant chr12-12718195-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1B	NM_004064.5 linkuse as main transcript	c.356T>C	p.Ile119Thr	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.356T>C	p.Ile119Thr	missense_variant	1/3	1	NM_004064.5	ENSP00000228872.4		P46527

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000533

AC:

132

AN:

247708

Hom.:

AF XY:

0.000512

AC XY:

AN XY:

134678

show subpopulations

Gnomad AFR exome

AF:

0.0000659

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.000760

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000715

AC:

1045

AN:

1460734

Hom.:

Cov.:

AF XY:

0.000681

AC XY:

495

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000171

Gnomad4 NFE exome

AF:

0.000839

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000611

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000848

Hom.:

Bravo

AF:

0.000812

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000453

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Observed in individuals with pituitary adenoma, neuroendocrine tumor, prostate cancer, and/or premature ovarian failure, but was also observed in unaffected controls (PMID: 15026335, 21575944, 22291433, 32232325, 35355569, 34313605); Published functional studies demonstrate expression and cellular localization similar to wild type, but also proteasome degradation resistance, increased protein stability, slightly delayed migration, and reduced RHOA and CDK2 interaction (PMID: 22291433, 32232325); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28824003, Hernndez-Ramrez_2019, 30990521, 24101221, 15607373, 21575944, 34426522, 15026335, 22291433, 34313605, Zuarth-Vazquez2023[abstract], 35355569, 32232325, 30065701, 36520683, 36149413, 30476936) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDKN1B p.Ile119Thr variant was identified in four individuals with varying phenotypes including prostate cancer, somatotropinoma, premature ovarian failure, and myeloproliferative syndrome (Chang_2004_PMID: 15026335; Tichomirowa_2012_PMID: 22291433; Ojeda_2011_PMID: 21575944; Pappa_2004_PMID: 15607373). Furthermore, this variant was also found in one heterozygous control (Tichomirowa_2012_PMID: 22291433). The variant was identified in dbSNP (ID: rs142833529) and ClinVar (classified as likely benign by Invitae and Illumina, and as uncertain significance by Ambry Genetics). The variant was not identified in the Cosmic database. The variant was identified in control databases in 143 of 265372 chromosomes at a frequency of 0.0005389 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 39 of 34986 chromosomes (freq: 0.001115), European (non-Finnish) in 94 of 116912 chromosomes (freq: 0.000804), Other in 4 of 6658 chromosomes (freq: 0.000601), European (Finnish) in 3 of 24810 chromosomes (freq: 0.000121), African in 2 of 22624 chromosomes (freq: 0.000088) and East Asian in 1 of 19096 chromosomes (freq: 0.000052), but was not observed in the Ashkenazi Jewish or South Asian populations. The p.Ile119 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CDKN1B: BP4, BS1:Supporting -

Multiple endocrine neoplasia type 4

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 08, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15607373, 21575944, 22291433] -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2022	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 05, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 06, 2021

DNA sequence analysis of the CDKN1B gene demonstrated a sequence change, c.356T>C, in exon 1 that results in an amino acid change, p.Ile119Thr. This sequence change has been described in an individual with myeloproliferative disorder (PMID: 15607373), an individual with Cushing√¢‚Ç¨‚Ñ¢s disease (PMID: 32232325), an individual with premature ovarian failure (PMID: 21575944), and in an individual with acromegaly (PMID: 22291433). This sequence change is present in the gnomAD database with a frequency of 0.11% in the Latino/Admixed American subpopulation (dbSNP rs142833529). The p.Ile119Thr change affects a moderately conserved amino acid residue located in a domain of the CDKN1B protein that is not known to be functional. The p.Ile119Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). An in vitro assay demonstrated protein instability and disruption of the scatter domain of CDKN1B for this sequence change (PMID: 32232325). Due to insufficient evidences, the clinical significance of the p.Ile119Thr change remains unknown at this time. -

CDKN1B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2022

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

0.055

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.49

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.45

PROVEAN

Benign

0.17

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.23

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0

B;.

Vest4

0.040

MVP

0.99

MPC

0.091

ClinPred

0.0055

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.23

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