11-2884069-G-C

Variant names:

• chr11-2884069-G-C
• rs531059713
• NM_001122630.2:c.853C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001122630.2(CDKN1C):​c.853C>G​(p.Pro285Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,399,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P285S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.197
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21353829).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

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.853C>G	p.Pro285Ala	missense	Exon 3 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.886C>G	p.Pro296Ala	missense	Exon 2 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.886C>G	p.Pro296Ala	missense	Exon 2 of 3	NP_001349403.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.853C>G	p.Pro285Ala	missense	Exon 3 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.886C>G	p.Pro296Ala	missense	Exon 2 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.886C>G	p.Pro296Ala	missense	Exon 2 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000100 AC: 14 AN: 1399648 Hom.: 0 Cov.: 32 AF XY: 0.00000724 AC XY: 5 AN XY: 691026

African (AFR) AF: 0.00 AC: 0 AN: 31354

American (AMR) AF: 0.00 AC: 0 AN: 36600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25088

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36364

South Asian (SAS) AF: 0.00 AC: 0 AN: 79678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5058

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1080558

Other (OTH) AF: 0.00 AC: 0 AN: 57928

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.2
DANN	Benign	0.65
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.20
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.17		Loss of glycosylation at P296 (P = 0.0319)
MVP		0.65
MPC		1.2
ClinPred		0.077	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.047
gMVP		0.088
Mutation Taster		=89/11	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: rs531059713; hg19: chr11-2905299;