11-2884840-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG

Variant names:

• chr11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGG
• rs878853638
• NM_001122630.2:c.587_616dupCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1 BP3 BP6_Very_Strong BS1 BS2

The NM_001122630.2(CDKN1C):​c.587_616dupCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG​(p.Ala196_Pro205dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 135,122 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. D206D) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000037 (0 hom., cov: 33)
• Consequence: CDKN1C NM_001122630.2 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.198
• 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 -15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_001122630.2
• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGG is Benign according to our data. Variant chr11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGG is described in ClinVar as Likely_benign. ClinVar VariationId is 524723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000037 (5/135122) while in subpopulation NFE AF = 0.0000793 (5/63074). AF 95% confidence interval is 0.0000312. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.587_616dupCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala196_Pro205dup	conservative_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.587_616dupCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala196_Pro205dup	conservative_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0000370 AC: 5 AN: 135122 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000793

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 22

GnomAD4 genome AF: 0.0000370 AC: 5 AN: 135122 Hom.: 0 Cov.: 33 AF XY: 0.0000456 AC XY: 3 AN XY: 65774

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000793 AC: 5 AN: 63074

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome Benign:1

Dec 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
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: rs878853638; hg19: chr11-2906070;