chr11-2884110-G-C

Variant names:

• chr11-2884110-G-C
• rs267606716
• NM_001122630.2:c.812C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001122630.2(CDKN1C):​c.812C>G​(p.Ser271*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S271S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.23
• Publications: 5 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2884110-G-C is Pathogenic according to our data. Variant chr11-2884110-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.812C>G	p.Ser271*	stop_gained	Exon 3 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.812C>G	p.Ser271*	stop_gained	Exon 3 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1369416 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 674180

African (AFR) AF: 0.00 AC: 0 AN: 28862

American (AMR) AF: 0.00 AC: 0 AN: 33710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24540

East Asian (EAS) AF: 0.00 AC: 0 AN: 33502

South Asian (SAS) AF: 0.00 AC: 0 AN: 77036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065612

Other (OTH) AF: 0.00 AC: 0 AN: 56500

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beckwith-Wiedemann syndrome Pathogenic:2

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser282*) in the CDKN1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN1C are known to be pathogenic (PMID: 20503313). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Beckwith-Wiedemann syndrome (PMID: 10424811, 19386358, 20503313). ClinVar contains an entry for this variant (Variation ID: 18445). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Mar 15, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 35 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26077438, 20503313, 35954470, 10424811) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	37
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0042	T;.
Eigen	Uncertain	0.49
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.38	.;T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.75	T
PhyloP100		1.2
PROVEAN	Benign	-0.030	N;.
REVEL	Benign	0.15
Sift	Benign	0.53	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0010	B;.
Vest4		0.15
MutPred		0.16		Gain of solvent accessibility (P = 0.0105);Gain of solvent accessibility (P = 0.0105);
MVP		0.75
ClinPred		0.51	D
GERP RS		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267606716; hg19: chr11-2905340;