11-2884951-G-C

Variant names:

• chr11-2884951-G-C
• rs113374868
• NM_001122630.2:c.506C>G

Variant summary

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

The NM_001122630.2(CDKN1C):​c.506C>G​(p.Pro169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P169S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0180
• Publications: 0 publications found

Genes affected

CDKN1C (HGNC:1786): (cyclin dependent kinase inhibitor 1C) This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

CDKN1C Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P, Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Beckwith-Wiedemann syndrome due to CDKN1C mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intrauterine growth restriction-short stature-early adult-onset diabetes syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Silver-Russell syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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=0.09082562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.506C>G	p.Pro169Arg	missense	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.539C>G	p.Pro180Arg	missense	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.539C>G	p.Pro180Arg	missense	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.506C>G	p.Pro169Arg	missense	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.539C>G	p.Pro180Arg	missense	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.539C>G	p.Pro180Arg	missense	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 875950 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 415760

African (AFR) AF: 0.00 AC: 0 AN: 17410

American (AMR) AF: 0.00 AC: 0 AN: 5924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10370

East Asian (EAS) AF: 0.00 AC: 0 AN: 18796

South Asian (SAS) AF: 0.00 AC: 0 AN: 16206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 753204

Other (OTH) AF: 0.00 AC: 0 AN: 34032

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:1

Feb 25, 2022

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 arginine, which is basic and polar, at codon 180 of the CDKN1C protein (p.Pro180Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CDKN1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 651967). 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.018
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.85	N
REVEL	Benign	0.039
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.35	B
Vest4		0.15
MutPred		0.33		Loss of sheet (P = 0.003)
MVP		0.60
MPC		1.3
ClinPred		0.093	T
GERP RS		0.64
Varity_R		0.039
gMVP		0.16
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs113374868; hg19: chr11-2906181;