11-2885047-G-C

Variant names:

• chr11-2885047-G-C
• rs754671425
• NM_001122630.2:c.410C>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.410C>G​(p.Pro137Arg) 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. P137Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.977
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18956032).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.410C>G	p.Pro137Arg	missense	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.443C>G	p.Pro148Arg	missense	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.443C>G	p.Pro148Arg	missense	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.410C>G	p.Pro137Arg	missense	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.443C>G	p.Pro148Arg	missense	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.443C>G	p.Pro148Arg	missense	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Beckwith-Wiedemann syndrome (2)
-	1	-	Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.98
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.22
MutPred		0.24		Loss of glycosylation at P148 (P = 0.0181)
MVP		0.16
MPC		1.3
ClinPred		0.19	T
GERP RS		0.65
Varity_R		0.098
gMVP		0.28
Mutation Taster		=94/6	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: rs754671425; hg19: chr11-2906277;