11-2883974-GC-GCC

Variant names:

• chr11-2883974-G-GC
• rs34289096
• NM_001122630.2:c.*5+24dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001122630.2(CDKN1C):​c.*5+24dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,553,768 control chromosomes in the GnomAD database, including 88,791 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7691 hom., cov: 0)
  • Exomes 𝑓: 0.33 (81100 hom.)
• Consequence: CDKN1C NM_001122630.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00
• Publications: 6 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), 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 -16 ACMG points.

• BP6: Variant 11-2883974-G-GC is Benign according to our data. Variant chr11-2883974-G-GC is described in ClinVar as Benign. ClinVar VariationId is 254879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.*5+24dupG		intron	N/A	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.*5+24dupG		intron	N/A	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.*5+24dupG		intron	N/A	NP_001349403.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.*5+24dupG		intron	N/A	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.*5+24dupG		intron	N/A	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.*5+24dupG		intron	N/A	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46062 AN: 151524 Hom.: 7695 Cov.: 0

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.372

GnomAD2 exomes AF: 0.359 AC: 55898 AN: 155866 AF XY: 0.362

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.332 AC: 465505 AN: 1402128 Hom.: 81100 Cov.: 32 AF XY: 0.334 AC XY: 231464 AN XY: 692560

African (AFR) AF: 0.226 AC: 7277 AN: 32250

American (AMR) AF: 0.338 AC: 12602 AN: 37330

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 13329 AN: 25180

East Asian (EAS) AF: 0.669 AC: 24379 AN: 36418

South Asian (SAS) AF: 0.405 AC: 32443 AN: 80190

European-Finnish (FIN) AF: 0.245 AC: 11288 AN: 45988

Middle Eastern (MID) AF: 0.447 AC: 2527 AN: 5656

European-Non Finnish (NFE) AF: 0.315 AC: 340694 AN: 1081046

Other (OTH) AF: 0.361 AC: 20966 AN: 58070

GnomAD4 genome AF: 0.304 AC: 46070 AN: 151640 Hom.: 7691 Cov.: 0 AF XY: 0.307 AC XY: 22715 AN XY: 74106

African (AFR) AF: 0.225 AC: 9334 AN: 41422

American (AMR) AF: 0.330 AC: 5037 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1893 AN: 3462

East Asian (EAS) AF: 0.661 AC: 3360 AN: 5082

South Asian (SAS) AF: 0.402 AC: 1933 AN: 4808

European-Finnish (FIN) AF: 0.245 AC: 2572 AN: 10502

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.306 AC: 20723 AN: 67790

Other (OTH) AF: 0.372 AC: 783 AN: 2104

Alfa AF: 0.245 Hom.: 952

Bravo AF: 0.312

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Beckwith-Wiedemann syndrome (1)
-	-	1	CDKN1C-related disorder (1)
-	-	1	IMAGe syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34289096; hg19: chr11-2905204;