NM_001122630.2:c.573_596delGGCCCCGGCCCCGGCCCCGGCCCC

Variant names:

• chr11-2884860-GGGGGCCGGGGCCGGGGCCGGGGCC-G
• rs759134767
• NM_001122630.2:c.573_596delGGCCCCGGCCCCGGCCCCGGCCCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001122630.2(CDKN1C):​c.573_596delGGCCCCGGCCCCGGCCCCGGCCCC​(p.Ala192_Pro199del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000114 in 879,570 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P191P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• 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 -1 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.573_596delGGCCCCGGCCCCGGCCCCGGCCCC	p.Ala192_Pro199del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.606_629delGGCCCCGGCCCCGGCCCCGGCCCC	p.Ala203_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.606_629delGGCCCCGGCCCCGGCCCCGGCCCC	p.Ala203_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.573_596delGGCCCCGGCCCCGGCCCCGGCCCC	p.Ala192_Pro199del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.606_629delGGCCCCGGCCCCGGCCCCGGCCCC	p.Ala203_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.606_629delGGCCCCGGCCCCGGCCCCGGCCCC	p.Ala203_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000114 AC: 1 AN: 879570 Hom.: 0 AF XY: 0.00000241 AC XY: 1 AN XY: 415602

African (AFR) AF: 0.00 AC: 0 AN: 17080

American (AMR) AF: 0.00 AC: 0 AN: 4070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8740

East Asian (EAS) AF: 0.00 AC: 0 AN: 15382

South Asian (SAS) AF: 0.00 AC: 0 AN: 17524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2124

European-Non Finnish (NFE) AF: 0.00000130 AC: 1 AN: 770300

Other (OTH) AF: 0.00 AC: 0 AN: 32002

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

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

Other links and lift over

dbSNP: rs759134767; hg19: chr11-2906090;