11-2884010-C-T

Variant names:

• chr11-2884010-C-T
• rs2133779878
• NM_001122630.2:c.912G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001362475.2(CDKN1C):​c.380G>A​(p.Cys127Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C127F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN1C NM_001362475.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.646
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• IMAGe syndrome

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41809076).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001362475.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.912G>A	p.Leu304Leu	synonymous	Exon 3 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_001362475.2		c.380G>A	p.Cys127Tyr	missense	Exon 3 of 4	NP_001349404.1	A0A2R8YFP9
	CDKN1C	NM_000076.2		c.945G>A	p.Leu315Leu	synonymous	Exon 2 of 3	NP_000067.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.912G>A	p.Leu304Leu	synonymous	Exon 3 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.945G>A	p.Leu315Leu	synonymous	Exon 2 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.945G>A	p.Leu315Leu	synonymous	Exon 2 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405996 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 694744

African (AFR) AF: 0.00 AC: 0 AN: 32222

American (AMR) AF: 0.00 AC: 0 AN: 37094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36776

South Asian (SAS) AF: 0.00 AC: 0 AN: 80140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1084062

Other (OTH) AF: 0.00 AC: 0 AN: 58270

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.33	D
PhyloP100		0.65
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.97	D
Vest4		0.31
MutPred		0.14		Gain of phosphorylation at C127 (P = 0.0279)
MVP		0.69
ClinPred		0.55	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -2

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

Other links and lift over

dbSNP: rs2133779878; hg19: chr11-2905240;