11-2885138-G-A

Variant names:

• chr11-2885138-G-A
• rs772684721
• NM_001122630.2:c.319C>T

Variant summary

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

The ENST00000440480.8(CDKN1C):​c.319C>T​(p.Pro107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 1,345,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P107A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CDKN1C ENST00000440480.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0310
• Publications: 1 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=0.16741663).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000440480.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.319C>T	p.Pro107Ser	missense	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.352C>T	p.Pro118Ser	missense	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.352C>T	p.Pro118Ser	missense	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.319C>T	p.Pro107Ser	missense	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.352C>T	p.Pro118Ser	missense	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.352C>T	p.Pro118Ser	missense	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1345648 Hom.: 0 Cov.: 31 AF XY: 0.00000453 AC XY: 3 AN XY: 662392

African (AFR) AF: 0.00 AC: 0 AN: 28242

American (AMR) AF: 0.00 AC: 0 AN: 29984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22730

East Asian (EAS) AF: 0.00 AC: 0 AN: 33632

South Asian (SAS) AF: 0.0000275 AC: 2 AN: 72824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4274

European-Non Finnish (NFE) AF: 9.40e-7 AC: 1 AN: 1064300

Other (OTH) AF: 0.00 AC: 0 AN: 56128

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.031
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.091
Sift	Benign	0.28	T
Sift4G	Benign	0.10	T
Polyphen		0.035	B
Vest4		0.058
MutPred		0.27		Loss of catalytic residue at P117 (P = 0.0175)
MVP		0.50
MPC		1.3
ClinPred		0.048	T
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.25
Mutation Taster		=99/1	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: rs772684721; hg19: chr11-2906368;