11-2884872-CGGGGCCGGGGCCGGGGCT-CGGGGCCGGGGCCGGGGCTGGGGCCGGGGCCGGGGCT

Variant names:

• chr11-2884872-C-CGGGGCCGGGGCCGGGGCT
• rs878853636
• NM_001122630.2:c.567_584dupAGCCCCGGCCCCGGCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP3 BP6

The NM_001122630.2(CDKN1C):​c.567_584dupAGCCCCGGCCCCGGCCCC​(p.Pro195_Ala196insAlaProAlaProAlaPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P195P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.519
• 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 36 uncertain in NM_001122630.2
• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884872-C-CGGGGCCGGGGCCGGGGCT is Benign according to our data. Variant chr11-2884872-C-CGGGGCCGGGGCCGGGGCT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1097288.

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.567_584dupAGCCCCGGCCCCGGCCCC	p.Pro195_Ala196insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.600_617dupAGCCCCGGCCCCGGCCCC	p.Pro206_Ala207insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.600_617dupAGCCCCGGCCCCGGCCCC	p.Pro206_Ala207insAlaProAlaProAlaPro	disruptive_inframe_insertion	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.567_584dupAGCCCCGGCCCCGGCCCC	p.Pro195_Ala196insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.600_617dupAGCCCCGGCCCCGGCCCC	p.Pro206_Ala207insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.600_617dupAGCCCCGGCCCCGGCCCC	p.Pro206_Ala207insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000142 AC: 1 AN: 703984 Hom.: 0 Cov.: 12 AF XY: 0.00000302 AC XY: 1 AN XY: 330716

African (AFR) AF: 0.00 AC: 0 AN: 13604

American (AMR) AF: 0.00 AC: 0 AN: 2164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5530

East Asian (EAS) AF: 0.00 AC: 0 AN: 6306

South Asian (SAS) AF: 0.00 AC: 0 AN: 14750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1576

European-Non Finnish (NFE) AF: 0.00000159 AC: 1 AN: 630754

Other (OTH) AF: 0.00 AC: 0 AN: 24172

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52

Splicing

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

Other links and lift over

dbSNP: rs878853636; hg19: chr11-2906102;