chr11-2884917-G-GGCCGGAGCCGGA

Variant names:

• chr11-2884917-G-GGCCGGAGCCGGA
• rs878853632
• NM_001122630.2:c.528_539dupTCCGGCTCCGGC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001122630.2(CDKN1C):​c.528_539dupTCCGGCTCCGGC​(p.Ala180_Pro181insProAlaProAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 738,432 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A180A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.823
• 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884917-G-GGCCGGAGCCGGA is Benign according to our data. Variant chr11-2884917-G-GGCCGGAGCCGGA is described in ClinVar as Likely_benign. ClinVar VariationId is 1161932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 11 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.528_539dupTCCGGCTCCGGC	p.Ala180_Pro181insProAlaProAla	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.561_572dupTCCGGCTCCGGC	p.Ala191_Pro192insProAlaProAla	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.561_572dupTCCGGCTCCGGC	p.Ala191_Pro192insProAlaProAla	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.528_539dupTCCGGCTCCGGC	p.Ala180_Pro181insProAlaProAla	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.561_572dupTCCGGCTCCGGC	p.Ala191_Pro192insProAlaProAla	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.561_572dupTCCGGCTCCGGC	p.Ala191_Pro192insProAlaProAla	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000149 AC: 11 AN: 738432 Hom.: 0 Cov.: 10 AF XY: 0.0000144 AC XY: 5 AN XY: 348430

African (AFR) AF: 0.00 AC: 0 AN: 12778

American (AMR) AF: 0.00 AC: 0 AN: 3198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6600

East Asian (EAS) AF: 0.00 AC: 0 AN: 7658

South Asian (SAS) AF: 0.00 AC: 0 AN: 14612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1710

European-Non Finnish (NFE) AF: 0.0000167 AC: 11 AN: 657244

Other (OTH) AF: 0.00 AC: 0 AN: 26366

GnomAD4 genome Cov.: 32

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		-0.82

Splicing

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

Other links and lift over

dbSNP: rs878853632; hg19: chr11-2906147;