11-2884840-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG

Variant names:

• chr11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCCGGGG
• rs878853638
• NM_001122630.2:c.575_616dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP3 BP6_Moderate

The NM_001122630.2(CDKN1C):​c.575_616dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG​(p.Ala192_Pro205dup) variant causes a conservative 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. D206D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDKN1C NM_001122630.2 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.198
• 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_001122630.2
• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCCGGGG is Benign according to our data. Variant chr11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCCGGGG is described in ClinVar as Likely_benign. ClinVar VariationId is 1619361.Status of the report is criteria_provided_single_submitter, 1 stars.

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.575_616dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala192_Pro205dup	conservative_inframe_insertion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.608_649dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala203_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.608_649dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala203_Pro216dup	conservative_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.575_616dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala192_Pro205dup	conservative_inframe_insertion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.608_649dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala203_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.608_649dupCCCCGGCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala203_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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
PhyloP100		-0.20

Splicing

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

Other links and lift over

dbSNP: rs878853638; hg19: chr11-2906070;