rs143992355

Variant names:

• chr11-2885574-C-T
• rs143992355
• ENST00000414822.8:c.-85G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000414822.8(CDKN1C):​c.-85G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,499,538 control chromosomes in the GnomAD database, including 1,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (101 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1186 hom.)
• Consequence: CDKN1C ENST00000414822.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0310
• Publications: 7 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-2885574-C-T is Benign according to our data. Variant chr11-2885574-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0276 (4205/152238) while in subpopulation NFE AF = 0.0397 (2697/67994). AF 95% confidence interval is 0.0384. There are 101 homozygotes in GnomAd4. There are 1888 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4205 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000414822.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.-11+60G>A		intron	N/A	NP_001116102.1
	CDKN1C	NM_000076.2		c.-85G>A		5_prime_UTR	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.-85G>A		5_prime_UTR	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000414822.8	TSL:1	c.-85G>A		5_prime_UTR	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.-85G>A		5_prime_UTR	Exon 1 of 3	ENSP00000411552.2
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.-11+60G>A		intron	N/A	ENSP00000411257.2

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4209 AN: 152122 Hom.: 101 Cov.: 33

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0909

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0388

GnomAD4 exome AF: 0.0386 AC: 52059 AN: 1347300 Hom.: 1186 Cov.: 25 AF XY: 0.0378 AC XY: 25066 AN XY: 663422

African (AFR) AF: 0.00756 AC: 233 AN: 30830

American (AMR) AF: 0.0256 AC: 883 AN: 34542

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 2096 AN: 23936

East Asian (EAS) AF: 0.00 AC: 0 AN: 35432

South Asian (SAS) AF: 0.0101 AC: 773 AN: 76224

European-Finnish (FIN) AF: 0.0153 AC: 505 AN: 32938

Middle Eastern (MID) AF: 0.0519 AC: 229 AN: 4414

European-Non Finnish (NFE) AF: 0.0429 AC: 45180 AN: 1052596

Other (OTH) AF: 0.0383 AC: 2160 AN: 56388

GnomAD4 genome AF: 0.0276 AC: 4205 AN: 152238 Hom.: 101 Cov.: 33 AF XY: 0.0254 AC XY: 1888 AN XY: 74422

African (AFR) AF: 0.00703 AC: 292 AN: 41564

American (AMR) AF: 0.0365 AC: 558 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0909 AC: 315 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4818

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10616

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0397 AC: 2697 AN: 67994

Other (OTH) AF: 0.0384 AC: 81 AN: 2108

Alfa AF: 0.0310 Hom.: 7

Bravo AF: 0.0289

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 27, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Beckwith-Wiedemann syndrome Benign:2

Jul 14, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 10424811)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		-0.031
PromoterAI		-0.046	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs143992355; hg19: chr11-2906804;