11-2884119-C-T

Variant names:

• chr11-2884119-C-T
• rs318240750
• NM_001122630.2:c.803G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000076.2(CDKN1C):​c.836G>A​(p.Arg279His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R279P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_000076.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000076.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2884119-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 35530.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36510265).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.803G>A	p.Arg268His	missense	Exon 3 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.836G>A	p.Arg279His	missense	Exon 2 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.836G>A	p.Arg279His	missense	Exon 2 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.803G>A	p.Arg268His	missense	Exon 3 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.836G>A	p.Arg279His	missense	Exon 2 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.836G>A	p.Arg279His	missense	Exon 2 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.42e-7 AC: 1 AN: 1347742 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 662212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27772

American (AMR) AF: 0.00 AC: 0 AN: 31662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23968

East Asian (EAS) AF: 0.0000315 AC: 1 AN: 31722

South Asian (SAS) AF: 0.00 AC: 0 AN: 75312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1053272

Other (OTH) AF: 0.00 AC: 0 AN: 55452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0096	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.19	D
PhyloP100		4.1
PROVEAN	Benign	0.31	N
REVEL	Benign	0.20
Sift	Benign	0.054	T
Sift4G	Benign	0.44	T
Polyphen		0.65	P
Vest4		0.20
MutPred		0.22		Gain of phosphorylation at A91 (P = 0.0082)
MVP		0.66
ClinPred		0.97	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.44
Mutation Taster		=33/67	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: rs318240750; hg19: chr11-2905349;