11-2884058-G-T

Variant names:

• chr11-2884058-G-T
• rs1554937479
• NM_001122630.2:c.864C>A

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.864C>A​(p.Ser288Arg) 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. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S288G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.577
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• 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=0.18814334).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.864C>A	p.Ser288Arg	missense	Exon 3 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.897C>A	p.Ser299Arg	missense	Exon 2 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.897C>A	p.Ser299Arg	missense	Exon 2 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.864C>A	p.Ser288Arg	missense	Exon 3 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.897C>A	p.Ser299Arg	missense	Exon 2 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.897C>A	p.Ser299Arg	missense	Exon 2 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691842

African (AFR) AF: 0.00 AC: 0 AN: 31562

American (AMR) AF: 0.00 AC: 0 AN: 36742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 36484

South Asian (SAS) AF: 0.00 AC: 0 AN: 79862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081046

Other (OTH) AF: 0.00 AC: 0 AN: 58004

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.70
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.47	T
PhyloP100		0.58
PROVEAN	Benign	0.37	N
REVEL	Benign	0.15
Sift	Benign	0.039	D
Sift4G	Benign	1.0	T
Polyphen		0.45	B
Vest4		0.32
MutPred		0.21		Gain of solvent accessibility (P = 0.0246)
MVP		0.38
ClinPred		0.15	T
GERP RS		-0.067
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.16
Mutation Taster		=98/2	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: rs1554937479; hg19: chr11-2905288;