ENST00000414822.8:c.12G>T

Variant names:

• chr11-2885478-C-A
• ENST00000414822.8:c.12G>T
• CDKN1C p.Ala4Ala

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The ENST00000414822.8(CDKN1C):​c.12G>T​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C ENST00000414822.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP7: Synonymous conserved (PhyloP=0.098 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000414822.8. 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.-10-12G>T		intron	N/A	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.12G>T	p.Ala4Ala	synonymous	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.12G>T	p.Ala4Ala	synonymous	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.12G>T	p.Ala4Ala	synonymous	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.12G>T	p.Ala4Ala	synonymous	Exon 1 of 3	ENSP00000411552.2	P49918-1
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.-10-12G>T		intron	N/A	ENSP00000411257.2	P49918-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1391644 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686670

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

American (AMR) AF: 0.00 AC: 0 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

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: 41476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078986

Other (OTH) AF: 0.00 AC: 0 AN: 57970

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		0.098
PromoterAI		0.00030	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-2906708;