rs1324090653

Variant names:

• chr11-2884972-ACCGGAG-A
• rs1324090653
• NM_001122630.2:c.479_484delCTCCGG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_001122630.2(CDKN1C):​c.479_484delCTCCGG​(p.Ala160_Pro161del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000711 in 591,020 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A160A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000057 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.99
• 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: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884972-ACCGGAG-A is Benign according to our data. Variant chr11-2884972-ACCGGAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 524749.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.479_484delCTCCGG	p.Ala160_Pro161del	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.479_484delCTCCGG	p.Ala160_Pro161del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0000567 AC: 5 AN: 88244 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000332

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000736 AC: 37 AN: 502776 Hom.: 0 AF XY: 0.0000712 AC XY: 17 AN XY: 238848

⚠️ 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: 15864

American (AMR) AF: 0.00 AC: 0 AN: 4070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5652

East Asian (EAS) AF: 0.00 AC: 0 AN: 18394

South Asian (SAS) AF: 0.0000885 AC: 1 AN: 11294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13852

Middle Eastern (MID) AF: 0.00149 AC: 2 AN: 1342

European-Non Finnish (NFE) AF: 0.0000827 AC: 34 AN: 411232

Other (OTH) AF: 0.00 AC: 0 AN: 21076

⚠️ 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 AF: 0.0000567 AC: 5 AN: 88244 Hom.: 0 Cov.: 22 AF XY: 0.0000461 AC XY: 2 AN XY: 43426

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000332 AC: 1 AN: 30110

American (AMR) AF: 0.00 AC: 0 AN: 8684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1622

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 160

European-Non Finnish (NFE) AF: 0.000118 AC: 4 AN: 33842

Other (OTH) AF: 0.00 AC: 0 AN: 1116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000993999), which strongly suggests a high chance of mosaicism in these individuals.

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

Jan 06, 2025

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
PhyloP100		2.0
Mutation Taster		=167/33	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1324090653; hg19: chr11-2906202;