chr11-2885359-C-T

Variant names:

• chr11-2885359-C-T
• rs1477382841
• NM_001122630.2:c.98G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001122630.2(CDKN1C):​c.98G>A​(p.Arg33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R33C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 2 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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_001122630.2
• PM2: Very rare variant in population databases, with high coverage

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.98G>A	p.Arg33His	missense	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.131G>A	p.Arg44His	missense	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.131G>A	p.Arg44His	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.98G>A	p.Arg33His	missense	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.131G>A	p.Arg44His	missense	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.131G>A	p.Arg44His	missense	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435874 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712564

African (AFR) AF: 0.00 AC: 0 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 42032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 38188

South Asian (SAS) AF: 0.00 AC: 0 AN: 82928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1101934

Other (OTH) AF: 0.00 AC: 0 AN: 59436

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:1

Jun 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CDKN1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 44 of the CDKN1C protein (p.Arg44His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.56		Loss of phosphorylation at S43 (P = 0.1073)
MVP		0.88
MPC		2.8
ClinPred		0.99	D
GERP RS		2.6
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.84
Mutation Taster		=83/17	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: rs1477382841; hg19: chr11-2906589;