11-2884884-CGGGGCT-CGGGGCTGGGGCT

Variant names:

• chr11-2884884-C-CGGGGCT
• rs1060503860
• NM_001122630.2:c.567_572dupAGCCCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001122630.2(CDKN1C):​c.567_572dupAGCCCC​(p.Pro191_Ala192insAlaPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 140,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P191P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0210
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-2884884-C-CGGGGCT is Benign according to our data. Variant chr11-2884884-C-CGGGGCT is described in ClinVar as [Likely_benign]. Clinvar id is 412847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000057 (8/140386) while in subpopulation SAS AF = 0.00111 (5/4486). AF 95% confidence interval is 0.000439. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.567_572dupAGCCCC	p.Pro191_Ala192insAlaPro	disruptive_inframe_insertion	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.567_572dupAGCCCC	p.Pro191_Ala192insAlaPro	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0000570 AC: 8 AN: 140322 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000312

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000257 AC: 19 AN: 738040 Hom.: 0 Cov.: 11 AF XY: 0.0000231 AC XY: 8 AN XY: 346914

African (AFR) AF: 0.00 AC: 0 AN: 13462

American (AMR) AF: 0.00 AC: 0 AN: 2094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5620

East Asian (EAS) AF: 0.000937 AC: 5 AN: 5336

South Asian (SAS) AF: 0.000204 AC: 3 AN: 14720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1578

European-Non Finnish (NFE) AF: 0.00000301 AC: 2 AN: 664862

Other (OTH) AF: 0.000355 AC: 9 AN: 25332

GnomAD4 genome AF: 0.0000570 AC: 8 AN: 140386 Hom.: 0 Cov.: 33 AF XY: 0.0000877 AC XY: 6 AN XY: 68386

African (AFR) AF: 0.00 AC: 0 AN: 38276

American (AMR) AF: 0.00 AC: 0 AN: 14038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.000212 AC: 1 AN: 4728

South Asian (SAS) AF: 0.00111 AC: 5 AN: 4486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000312 AC: 2 AN: 64142

Other (OTH) AF: 0.00 AC: 0 AN: 1956

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

Jan 23, 2025

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		-0.021
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1060503860; hg19: chr11-2906114;