11-2885479-G-C

Variant names:

• chr11-2885479-G-C
• rs201368350
• ENST00000414822.8:c.11C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000076.2(CDKN1C):​c.11C>G​(p.Ala4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,391,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDKN1C NM_000076.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.915
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17544565).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000076.2. 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.-10-13C>G		intron	N/A	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.11C>G	p.Ala4Gly	missense	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.11C>G	p.Ala4Gly	missense	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000414822.8	TSL:1	c.11C>G	p.Ala4Gly	missense	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.11C>G	p.Ala4Gly	missense	Exon 1 of 3	ENSP00000411552.2	P49918-1
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.-10-13C>G		intron	N/A	ENSP00000411257.2	P49918-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000122 AC: 17 AN: 1391584 Hom.: 0 Cov.: 31 AF XY: 0.0000160 AC XY: 11 AN XY: 686654

African (AFR) AF: 0.00 AC: 0 AN: 31602

American (AMR) AF: 0.00 AC: 0 AN: 35718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35770

South Asian (SAS) AF: 0.00 AC: 0 AN: 79260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000158 AC: 17 AN: 1078986

Other (OTH) AF: 0.00 AC: 0 AN: 57960

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.16
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.92
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.035	D
Sift4G	Uncertain	0.026	D
Polyphen		0.94	P
Vest4		0.059
MutPred		0.14		Loss of sheet (P = 0.0104)
MVP		0.62
MPC		1.8
ClinPred		0.20	T
GERP RS		-3.0
PromoterAI		-0.057	Neutral
Varity_R		0.079
gMVP		0.68
Mutation Taster		=30/70	disease causing

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: rs201368350; hg19: chr11-2906709;