11-2884961-C-T

Variant names:

• chr11-2884961-C-T
• rs1060500174
• NM_001122630.2:c.496G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001122630.2(CDKN1C):​c.496G>A​(p.Val166Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. V166A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.295
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08028954).

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.496G>A	p.Val166Ile	missense	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.529G>A	p.Val177Ile	missense	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.529G>A	p.Val177Ile	missense	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.496G>A	p.Val166Ile	missense	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.529G>A	p.Val177Ile	missense	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.529G>A	p.Val177Ile	missense	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146988 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000111 AC: 1 AN: 899956 Hom.: 0 Cov.: 13 AF XY: 0.00000233 AC XY: 1 AN XY: 428372

African (AFR) AF: 0.00 AC: 0 AN: 18260

American (AMR) AF: 0.00 AC: 0 AN: 6462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11014

East Asian (EAS) AF: 0.00 AC: 0 AN: 20676

South Asian (SAS) AF: 0.00 AC: 0 AN: 17154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2420

European-Non Finnish (NFE) AF: 0.00000130 AC: 1 AN: 769346

Other (OTH) AF: 0.00 AC: 0 AN: 35432

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 146988 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71630

African (AFR) AF: 0.00 AC: 0 AN: 40520

American (AMR) AF: 0.00 AC: 0 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66044

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Beckwith-Wiedemann syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.4
DANN	Benign	0.96
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.29
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.013
Sift	Benign	0.034	D
Sift4G	Benign	0.21	T
Polyphen		0.0030	B
Vest4		0.062
MutPred		0.32		Loss of catalytic residue at V177 (P = 8e-04)
MVP		0.50
MPC		1.1
ClinPred		0.057	T
GERP RS		0.56
Varity_R		0.047
gMVP		0.057
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: rs1060500174; hg19: chr11-2906191;