chr12-12718122-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_004064.5(CDKN1B):c.283C>T(p.Pro95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P95A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CDKN1B
NM_004064.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 1.85

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

multiple endocrine neoplasia type 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
multiple endocrine neoplasia
Inheritance: AD Classification: STRONG Submitted by: G2P
hereditary nonpolyposis colon cancer
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

CDKN1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.169738).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000151 (221/1461804) while in subpopulation EAS AF = 0.000277 (11/39700). AF 95% confidence interval is 0.000155. There are 0 homozygotes in GnomAdExome4. There are 92 alleles in the male GnomAdExome4 subpopulation. Median coverage is 51. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 3	ENST00000228872.9	NP_004055.1	P46527Q6I9V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 3	1	NM_004064.5	ENSP00000228872.4		P46527

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000879

AC:

AN:

250232

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

221

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000174

AC:

193

AN:

1112006

Other (OTH)

AF:

0.0000828

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41596

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000611

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 4

Uncertain:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 95 of the CDKN1B protein (p.Pro95Ser). This variant is present in population databases (rs188579132, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple neoplasia type 1 and Zollinger-Ellison syndrome (PMID: 19141585). ClinVar contains an entry for this variant (Variation ID: 404265). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 19141585). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKN1B c.283C>T (p.Pro95Ser) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant is reported to have reduced binding to GRB2 and was reported in an individual with hyperparathyroidism and Zollinger-Ellison syndrome (PMID: 19141585). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided

Uncertain:3

Mar 14, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with multiple endocrine neoplasia type 1 and was shown to impair binding to GRB2 (Agarwal et al., 2009); This variant is associated with the following publications: (PMID: 24819502, 20824794, 30065701, 22584700, 28824003, 34426522, 31980526, 19141585) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CDKN1B p.P95S variant was identified in one individual with Zollinger-Ellison syndrome (Agarwal_2009_PMID: 19141585). The variant was not identified in COSMIC but was identified in dbSNP (ID: rs188579132) and ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 23 of 281634 chromosomes at a frequency of 0.00008167, and was observed at the highest frequency in the European (non-Finnish) population in 18 of 128704 chromosomes (freq: 0.0001399) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.P95 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis shows that this variant results in reduced protein binding activity (Agarwal_2009_PMID: 19141585). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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. This variant is classified as a variant of uncertain significance. -

Jun 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, the variant has been reported in an individuals with Zollinger-Ellison Syndrome (PMID: 19141585 (2009) and multiple endocrine neoplasia (PMID: 31980526 (2020)). A functional study found that this variant reduced binding activity (PMID: 19141585 (2009)). The frequency of this variant in the general population, 0.00014 (18/128704 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Oct 19, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P95S variant (also known as c.283C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 283. The proline at codon 95 is replaced by serine, an amino acid with similar properties. This alteration was detected in one individual with features of Multiple Endocrine Neoplasia Type 1 syndrome, including hyperparathyroidism and Zollinger-Ellison syndrome (Agarwal SK et al. J. Clin. Endocrinol. Metab., 2009 May;94:1826-34). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

2.0

M;.

PhyloP100

1.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.70

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.18

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.0020

B;.

Vest4

0.090

MVP

0.95

MPC

0.077

ClinPred

0.056

GERP RS

5.4

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.36

Mutation Taster

=36/64

disease causing

(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