11-2884878-C-T

Variant names:

• chr11-2884878-C-T
• rs794726872
• NM_001122630.2:c.579G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001122630.2(CDKN1C):​c.579G>A​(p.Pro193Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P193P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0200
• 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: 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 (BayesDel_noAF=-0.64).
• BP6: Variant 11-2884878-C-T is Benign according to our data. Variant chr11-2884878-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193040.
• BP7: Synonymous conserved (PhyloP=0.02 with no splicing effect.

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.579G>A	p.Pro193Pro	synonymous	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.612G>A	p.Pro204Pro	synonymous	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.612G>A	p.Pro204Pro	synonymous	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.579G>A	p.Pro193Pro	synonymous	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.612G>A	p.Pro204Pro	synonymous	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.612G>A	p.Pro204Pro	synonymous	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.00000713 AC: 1 AN: 140226 Hom.: 0 Cov.: 33

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: 0.0000160

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 30 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000437 AC: 326 AN: 745240 Hom.: 0 Cov.: 11 AF XY: 0.000388 AC XY: 136 AN XY: 350442

⚠️ 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: 14208

American (AMR) AF: 0.000433 AC: 1 AN: 2310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5950

East Asian (EAS) AF: 0.00 AC: 0 AN: 6528

South Asian (SAS) AF: 0.000197 AC: 3 AN: 15254

European-Finnish (FIN) AF: 0.000178 AC: 1 AN: 5616

Middle Eastern (MID) AF: 0.000608 AC: 1 AN: 1646

European-Non Finnish (NFE) AF: 0.000460 AC: 307 AN: 667942

Other (OTH) AF: 0.000504 AC: 13 AN: 25786

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000713 AC: 1 AN: 140226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 68322

African (AFR) AF: 0.00 AC: 0 AN: 39344

American (AMR) AF: 0.00 AC: 0 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3266

East Asian (EAS) AF: 0.00 AC: 0 AN: 4870

South Asian (SAS) AF: 0.00 AC: 0 AN: 4548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000160 AC: 1 AN: 62568

Other (OTH) AF: 0.00 AC: 0 AN: 1926

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Beckwith-Wiedemann syndrome (2)
-	1	1	not provided (2)
-	-	1	CDKN1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.9
DANN	Benign	0.91
PhyloP100		0.020
Mutation Taster		=100/0	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: rs794726872; hg19: chr11-2906108; COSMIC: COSV100532266; COSMIC: COSV100532266;