rs878853634

chr11-2884878-CGGGGCCGGGGCT-Cchr11-2884878-CGGGGCCGGGGCT-CGGGGCCGGGGCTGGGGCCGGGGCT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001122630.2(CDKN1C):c.567_578del(p.Ala202_Pro205del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 885,706 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P189P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: CDKN1C NM_001122630.2 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.900

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 11-2884878-CGGGGCCGGGGCT-C is Benign according to our data. Variant chr11-2884878-CGGGGCCGGGGCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 236960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.567_578del	p.Ala202_Pro205del	inframe_deletion	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.567_578del	p.Ala202_Pro205del	inframe_deletion	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 545 AN: 140228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00168

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0105

Gnomad SAS AF: 0.00484

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000160

Gnomad OTH AF: 0.00260

GnomAD4 exome AF: 0.000415 AC: 309 AN: 745376 Hom.: 3 AF XY: 0.000385 AC XY: 135 AN XY: 350504

Gnomad4 AFR exome AF: 0.00901

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00551

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000913

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00393 AC: 551 AN: 140330 Hom.: 1 Cov.: 33 AF XY: 0.00378 AC XY: 259 AN XY: 68432

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00167

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0105

Gnomad4 SAS AF: 0.00484

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000160

Gnomad4 OTH AF: 0.00565

Alfa AF: 0.0000615 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 15, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDKN1C: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 13, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CDKN1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853634; hg19: chr11-2906108;