rs1249284743

Variant names:

• chr11-2884929-AGCCGGAGCCGGG-A
• rs1249284743
• NM_001122630.2:c.516_527delCCCGGCTCCGGC

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_001122630.2(CDKN1C):​c.516_527delCCCGGCTCCGGC​(p.Pro173_Ala176del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 863,578 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A172A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.514
• 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884929-AGCCGGAGCCGGG-A is Benign according to our data. Variant chr11-2884929-AGCCGGAGCCGGG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 454012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000403 (5/124008) while in subpopulation AFR AF = 0.0000963 (3/31154). AF 95% confidence interval is 0.0000255. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.516_527delCCCGGCTCCGGC	p.Pro173_Ala176del	disruptive_inframe_deletion	Exon 2 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.516_527delCCCGGCTCCGGC	p.Pro173_Ala176del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0000403 AC: 5 AN: 124008 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000963

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: 0.0000341

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000122 AC: 9 AN: 739570 Hom.: 0 AF XY: 0.0000143 AC XY: 5 AN XY: 350372

African (AFR) AF: 0.00 AC: 0 AN: 13174

American (AMR) AF: 0.00 AC: 0 AN: 4142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7756

East Asian (EAS) AF: 0.00 AC: 0 AN: 11362

South Asian (SAS) AF: 0.0000698 AC: 1 AN: 14324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1806

European-Non Finnish (NFE) AF: 0.0000124 AC: 8 AN: 647466

Other (OTH) AF: 0.00 AC: 0 AN: 27586

GnomAD4 genome AF: 0.0000403 AC: 5 AN: 124008 Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 2 AN XY: 60460

African (AFR) AF: 0.0000963 AC: 3 AN: 31154

American (AMR) AF: 0.00 AC: 0 AN: 13220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3090

East Asian (EAS) AF: 0.00 AC: 0 AN: 4274

South Asian (SAS) AF: 0.00 AC: 0 AN: 3930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.0000341 AC: 2 AN: 58626

Other (OTH) AF: 0.00 AC: 0 AN: 1714

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.51
Mutation Taster		=197/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1249284743; hg19: chr11-2906159;