NM_001122630.2:c.605_616delCCCCGGCCCCGG

Variant names:

• chr11-2884840-TCCGGGGCCGGGG-T
• rs772704243
• NM_001122630.2:c.605_616delCCCCGGCCCCGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP6_Moderate BS2

The NM_001122630.2(CDKN1C):​c.605_616delCCCCGGCCCCGG​(p.Ala202_Pro205del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,129,204 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. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A202A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.949
• 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 -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001122630.2
• BP6: Variant 11-2884840-TCCGGGGCCGGGG-T is Benign according to our data. Variant chr11-2884840-TCCGGGGCCGGGG-T is described in ClinVar as [Likely_benign]. Clinvar id is 412845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.605_616delCCCCGGCCCCGG	p.Ala202_Pro205del	disruptive_inframe_deletion	Exon 2 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.605_616delCCCCGGCCCCGG	p.Ala202_Pro205del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0000222 AC: 3 AN: 135124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000317

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 20 AN: 994080 Hom.: 0 AF XY: 0.0000210 AC XY: 10 AN XY: 475938

African (AFR) AF: 0.00 AC: 0 AN: 19300

American (AMR) AF: 0.00 AC: 0 AN: 6496

Ashkenazi Jewish (ASJ) AF: 0.0000832 AC: 1 AN: 12022

East Asian (EAS) AF: 0.0000562 AC: 1 AN: 17794

South Asian (SAS) AF: 0.00 AC: 0 AN: 29910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2614

European-Non Finnish (NFE) AF: 0.0000199 AC: 17 AN: 855052

Other (OTH) AF: 0.0000274 AC: 1 AN: 36526

GnomAD4 genome AF: 0.0000222 AC: 3 AN: 135124 Hom.: 0 Cov.: 33 AF XY: 0.0000152 AC XY: 1 AN XY: 65774

African (AFR) AF: 0.00 AC: 0 AN: 36342

American (AMR) AF: 0.0000722 AC: 1 AN: 13844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3296

East Asian (EAS) AF: 0.00 AC: 0 AN: 4188

South Asian (SAS) AF: 0.00 AC: 0 AN: 3958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.0000317 AC: 2 AN: 63076

Other (OTH) AF: 0.00 AC: 0 AN: 1874

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=198/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs772704243; hg19: chr11-2906070;