chr12-12718863-G-C

Variant names:

• chr12-12718863-G-C
• rs1260635377
• NM_004064.5:c.514G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004064.5(CDKN1B):​c.514G>C​(p.Glu172Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E172K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDKN1B NM_004064.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23315892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1B	NM_004064.5	c.514G>C	p.Glu172Gln	missense_variant	Exon 2 of 3	ENST00000228872.9	NP_004055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000228872.9	c.514G>C	p.Glu172Gln	missense_variant	Exon 2 of 3	1	NM_004064.5	ENSP00000228872.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia type 4 Uncertain:1

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 172 of the CDKN1B protein (p.Glu172Gln). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 536834). This variant has not been reported in the literature in individuals affected with CDKN1B-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		6.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T
Sift4G	Benign	0.46	T;T
Polyphen		1.0	D;.
Vest4		0.49
MutPred		0.20		Gain of MoRF binding (P = 0.023);.;
MVP		0.67
MPC		0.41
ClinPred		0.86	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.22
gMVP		0.19
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1260635377; hg19: chr12-12871797;