rs104894200

Variant names:

• chr11-2884750-G-A
• rs104894200
• NM_001122630.2:c.707C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2884750-G-A
• chr11-2884750-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122630.2(CDKN1C):​c.707C>T​(p.Ser236Leu) variant causes a missense 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S236S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22947139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.707C>T	p.Ser236Leu	missense_variant	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.707C>T	p.Ser236Leu	missense_variant	Exon 2 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: 1358826 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676074

African (AFR) AF: 0.00 AC: 0 AN: 28020

American (AMR) AF: 0.00 AC: 0 AN: 36010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23320

East Asian (EAS) AF: 0.00 AC: 0 AN: 31108

South Asian (SAS) AF: 0.00 AC: 0 AN: 79154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065206

Other (OTH) AF: 0.00 AC: 0 AN: 55264

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:1

Nov 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDKN1C protein function. ClinVar contains an entry for this variant (Variation ID: 404242). This variant has not been reported in the literature in individuals affected with CDKN1C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 247 of the CDKN1C protein (p.Ser247Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.60	.;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.34	N;N;.
PhyloP100		3.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.89	P;P;.
Vest4		0.076
MutPred		0.30		Loss of glycosylation at S247 (P = 4e-04);Loss of glycosylation at S247 (P = 4e-04);.;
MVP		0.49
MPC		1.1
ClinPred		0.64	D
GERP RS		1.9
Varity_R		0.14
gMVP		0.15
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs104894200; hg19: chr11-2905980;