NM_001122630.2:c.803G>T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_001122630.2(CDKN1C):​c.803G>T​(p.Arg268Leu) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 4.13
• Publications: 11 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_pathogenic. The variant received 7 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_001122630.2
• 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.
• PP5: Variant 11-2884119-C-A is Pathogenic according to our data. Variant chr11-2884119-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 192361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36121842). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.803G>T	p.Arg268Leu	missense	Exon 3 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.836G>T	p.Arg279Leu	missense	Exon 2 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.836G>T	p.Arg279Leu	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>T	p.Arg268Leu	missense	Exon 3 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.836G>T	p.Arg279Leu	missense	Exon 2 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.836G>T	p.Arg279Leu	missense	Exon 2 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1347742 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 662212

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: 0.00 AC: 0 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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Beckwith-Wiedemann syndrome (1)
-	-	-	IMAGe syndrome (1)
-	-	-	Silver-Russell syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Benign	0.97
DEOGEN2	Benign	0.0054	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.23	D
PhyloP100		4.1
PROVEAN	Benign	0.10	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.37	T
Polyphen		0.90	P
Vest4		0.21
MutPred		0.25		Gain of phosphorylation at A91 (P = 0.0187)
MVP		0.77
ClinPred		0.99	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.60
Mutation Taster		=2/98	disease causing (ClinVar)

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;