rs997267634

Variant names:

• chr11-2884908-TGGAGCCGGGGCC-T
• rs997267634
• NM_001122630.2:c.537_548delGGCCCCGGCTCC

Your query was ambiguous. Multiple possible variants found:

• chr11-2884908-TGGAGCCGGGGCC-T
• chr11-2884908-TGGAGCCGGGGCC-TGGAGCCGGGGCCGGAGCCGGGGCC

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.537_548delGGCCCCGGCTCC​(p.Ala180_Pro183del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000519 in 770,016 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. P179P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37
• 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 11-2884908-TGGAGCCGGGGCC-T is Benign according to our data. Variant chr11-2884908-TGGAGCCGGGGCC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1088193.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.537_548delGGCCCCGGCTCC	p.Ala180_Pro183del	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.537_548delGGCCCCGGCTCC	p.Ala180_Pro183del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0000171 AC: 2 AN: 116966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000658

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000306 AC: 2 AN: 653050 Hom.: 0 AF XY: 0.00000325 AC XY: 1 AN XY: 308004

⚠️ 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: 12252

American (AMR) AF: 0.00 AC: 0 AN: 2548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5534

East Asian (EAS) AF: 0.00 AC: 0 AN: 5630

South Asian (SAS) AF: 0.00 AC: 0 AN: 13018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1494

European-Non Finnish (NFE) AF: 0.00000343 AC: 2 AN: 583094

Other (OTH) AF: 0.00 AC: 0 AN: 23122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000171 AC: 2 AN: 116966 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 57200

African (AFR) AF: 0.0000658 AC: 2 AN: 30392

American (AMR) AF: 0.00 AC: 0 AN: 12568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2890

East Asian (EAS) AF: 0.00 AC: 0 AN: 3860

South Asian (SAS) AF: 0.00 AC: 0 AN: 3540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54984

Other (OTH) AF: 0.00 AC: 0 AN: 1612

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

Dec 18, 2021

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		1.4
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: rs997267634; hg19: chr11-2906138;