11-2884067-G-C

Variant names:

• chr11-2884067-G-C
• rs779172459
• NM_001122630.2:c.855C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The ENST00000440480.8(CDKN1C):​c.855C>G​(p.Pro285Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P285P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CDKN1C ENST00000440480.8 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0910
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15683922).
• BP6: Variant 11-2884067-G-C is Benign according to our data. Variant chr11-2884067-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 737973.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.091 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000440480.8. 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.855C>G	p.Pro285Pro	synonymous	Exon 3 of 4	NP_001116102.1
	CDKN1C	NM_001362475.2		c.323C>G	p.Pro108Arg	missense	Exon 3 of 4	NP_001349404.1
	CDKN1C	NM_000076.2		c.888C>G	p.Pro296Pro	synonymous	Exon 2 of 3	NP_000067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.855C>G	p.Pro285Pro	synonymous	Exon 3 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.888C>G	p.Pro296Pro	synonymous	Exon 2 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.888C>G	p.Pro296Pro	synonymous	Exon 2 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399938 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691158

African (AFR) AF: 0.00 AC: 0 AN: 31382

American (AMR) AF: 0.00 AC: 0 AN: 36608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25094

East Asian (EAS) AF: 0.00 AC: 0 AN: 36342

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5098

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080708

Other (OTH) AF: 0.00 AC: 0 AN: 57946

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	0.11
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	4.5
DANN	Benign	0.94
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.77	T
PhyloP100		0.091
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.072
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.40	T
Polyphen		0.028	B
Vest4		0.21
MutPred		0.32		Loss of loop (P = 0.0073)
MVP		0.32
ClinPred		0.053	T
GERP RS		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=92/8	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: rs779172459; hg19: chr11-2905297;