11-2885055-CGCCGGG-CGCCGGGGCCGGG

Variant names:

• chr11-2885055-C-CGCCGGG
• rs1201148541
• NM_001122630.2:c.396_401dupCCCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001122630.2(CDKN1C):​c.396_401dupCCCGGC​(p.Ala134_Ser135insProAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,193,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001122630.2

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.396_401dupCCCGGC	p.Ala134_Ser135insProAla	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.429_434dupCCCGGC	p.Ala145_Ser146insProAla	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.429_434dupCCCGGC	p.Ala145_Ser146insProAla	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.396_401dupCCCGGC	p.Ala134_Ser135insProAla	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.429_434dupCCCGGC	p.Ala145_Ser146insProAla	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.429_434dupCCCGGC	p.Ala145_Ser146insProAla	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 5034 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1193552 Hom.: 0 Cov.: 30 AF XY: 0.00000173 AC XY: 1 AN XY: 577442

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23148

American (AMR) AF: 0.00 AC: 0 AN: 9498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16166

East Asian (EAS) AF: 0.0000364 AC: 1 AN: 27464

South Asian (SAS) AF: 0.0000204 AC: 1 AN: 49098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3328

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 987336

Other (OTH) AF: 0.00 AC: 0 AN: 48988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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
PhyloP100		0.32

Splicing

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

Other links and lift over

dbSNP: rs1201148541; hg19: chr11-2906285;