rs878853630

chr11-2884908-TGGAGCCGGGGCCGGAGCCGGAGCC-Tchr11-2884908-TGGAGCCGGGGCCGGAGCCGGAGCC-TGGAGCCGGGGCCGGAGCCGGAGCCGGAGCCGGGGCCGGAGCCGGAGCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001122630.2(CDKN1C):c.525_548del(p.Ala176_Pro183del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 770,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P175P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.37

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 11-2884908-TGGAGCCGGGGCCGGAGCCGGAGCC-T is Benign according to our data. Variant chr11-2884908-TGGAGCCGGGGCCGGAGCCGGAGCC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236956.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BS2: High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.525_548del	p.Ala176_Pro183del	inframe_deletion	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.525_548del	p.Ala176_Pro183del	inframe_deletion	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.000274 AC: 32 AN: 116966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000398

Gnomad ASJ AF: 0.00138

Gnomad EAS AF: 0.000259

Gnomad SAS AF: 0.000282

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 138 AN: 653046 Hom.: 0 AF XY: 0.000227 AC XY: 70 AN XY: 308004

Gnomad4 AFR exome AF: 0.000163

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000542

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000768

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.000432

GnomAD4 genome AF: 0.000282 AC: 33 AN: 117044 Hom.: 0 Cov.: 32 AF XY: 0.000314 AC XY: 18 AN XY: 57292

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.000398

Gnomad4 ASJ AF: 0.00138

Gnomad4 EAS AF: 0.000260

Gnomad4 SAS AF: 0.000567

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 09, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

This alteration is classified as likely 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

CDKN1C: BS1 -

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: rs878853630; hg19: chr11-2906138;