11-2883776-A-G

Variant names:

• chr11-2883776-A-G
• rs1240499527
• NM_001122630.2:c.*145T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4 BS1_Supporting BS2

The NM_001362475.2(CDKN1C):​c.526T>C​(p.Ter176Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,329,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CDKN1C NM_001362475.2 stop_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.614
• 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: 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 -3 ACMG points.

• PM4: Stoplost variant in NM_001362475.2 Downstream stopcodon found after 63 codons.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000143 (19/1329376) while in subpopulation MID AF = 0.000464 (2/4312). AF 95% confidence interval is 0.000082. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001362475.2. 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.*145T>C		3_prime_UTR	Exon 4 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_001362475.2		c.526T>C	p.Ter176Argext*?	stop_lost	Exon 4 of 4	NP_001349404.1	A0A2R8YFP9
	CDKN1C	NM_000076.2		c.*145T>C		3_prime_UTR	Exon 3 of 3	NP_000067.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.*145T>C		3_prime_UTR	Exon 4 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.*140T>C		3_prime_UTR	Exon 3 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.*145T>C		3_prime_UTR	Exon 3 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000143 AC: 19 AN: 1329376 Hom.: 0 Cov.: 30 AF XY: 0.0000153 AC XY: 10 AN XY: 652792

African (AFR) AF: 0.00 AC: 0 AN: 28590

American (AMR) AF: 0.0000437 AC: 1 AN: 22902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21606

East Asian (EAS) AF: 0.00 AC: 0 AN: 35052

South Asian (SAS) AF: 0.00 AC: 0 AN: 70376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34056

Middle Eastern (MID) AF: 0.000464 AC: 2 AN: 4312

European-Non Finnish (NFE) AF: 0.0000132 AC: 14 AN: 1057180

Other (OTH) AF: 0.0000362 AC: 2 AN: 55302

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.81
FATHMM_MKL	Benign	0.38	N
PhyloP100		0.61
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1240499527; hg19: chr11-2905006;