rs1554937506

Variant names:

• chr11-2884106-C-T
• rs1554937506
• NM_001122630.2:c.816G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_001122630.2(CDKN1C):​c.816G>A​(p.Ala272Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000945 in 1,376,224 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.631
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32239535).
• BP6: Variant 11-2884106-C-T is Benign according to our data. Variant chr11-2884106-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 524718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.816G>A	p.Ala272Ala	synonymous_variant	Exon 3 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.816G>A	p.Ala272Ala	synonymous_variant	Exon 3 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000945 AC: 13 AN: 1376224 Hom.: 0 Cov.: 32 AF XY: 0.0000118 AC XY: 8 AN XY: 677960

African (AFR) AF: 0.00 AC: 0 AN: 29298

American (AMR) AF: 0.00 AC: 0 AN: 34336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24650

East Asian (EAS) AF: 0.00 AC: 0 AN: 34038

South Asian (SAS) AF: 0.00 AC: 0 AN: 77530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4330

European-Non Finnish (NFE) AF: 0.0000122 AC: 13 AN: 1069310

Other (OTH) AF: 0.00 AC: 0 AN: 56832

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.57	.;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.051	T
PhyloP100		-0.63
PROVEAN	Benign	-0.33	N;.
REVEL	Benign	0.26
Sift	Benign	0.080	T;.
Sift4G	Benign	0.32	T;.
Polyphen		0.99	D;.
Vest4		0.17
MutPred		0.26		Loss of loop (P = 0.0075);Loss of loop (P = 0.0075);
MVP		0.81
ClinPred		0.31	T
GERP RS		0.93
Mutation Taster		=89/11	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: rs1554937506; hg19: chr11-2905336;