rs1380480846

Variant names:

• chr11-2884848-CGGGGCCGGGGCG-C
• rs1380480846
• NM_001122630.2:c.597_608delCGCCCCGGCCCC

Your query was ambiguous. Multiple possible variants found:

• chr11-2884848-CGGGGCCGGGGCG-C
• chr11-2884848-CGGGGCCGGGGCG-CGGGGCCGGGGCGGGGGCCGGGGCG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP3 BP6_Very_Strong

The NM_001122630.2(CDKN1C):​c.597_608delCGCCCCGGCCCC​(p.Ala200_Pro203del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 142,262 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. P199P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.74
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• 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 -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_001122630.2
• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884848-CGGGGCCGGGGCG-C is Benign according to our data. Variant chr11-2884848-CGGGGCCGGGGCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 696956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.597_608delCGCCCCGGCCCC	p.Ala200_Pro203del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.630_641delCGCCCCGGCCCC	p.Ala211_Pro214del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.630_641delCGCCCCGGCCCC	p.Ala211_Pro214del	disruptive_inframe_deletion	Exon 1 of 3	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.597_608delCGCCCCGGCCCC	p.Ala200_Pro203del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.630_641delCGCCCCGGCCCC	p.Ala211_Pro214del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.630_641delCGCCCCGGCCCC	p.Ala211_Pro214del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.0000281 AC: 4 AN: 142166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.000225

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000515

GnomAD2 exomes AF: 0.00 AC: 0 AN: 7858 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000376 AC: 37 AN: 982740 Hom.: 0 AF XY: 0.0000344 AC XY: 16 AN XY: 465514

African (AFR) AF: 0.00 AC: 0 AN: 19278

American (AMR) AF: 0.00 AC: 0 AN: 5520

Ashkenazi Jewish (ASJ) AF: 0.0000938 AC: 1 AN: 10658

East Asian (EAS) AF: 0.000269 AC: 5 AN: 18572

South Asian (SAS) AF: 0.0000455 AC: 1 AN: 21986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2440

European-Non Finnish (NFE) AF: 0.0000340 AC: 29 AN: 853022

Other (OTH) AF: 0.0000275 AC: 1 AN: 36386

GnomAD4 genome AF: 0.0000281 AC: 4 AN: 142262 Hom.: 0 Cov.: 33 AF XY: 0.0000288 AC XY: 2 AN XY: 69348

African (AFR) AF: 0.0000256 AC: 1 AN: 39134

American (AMR) AF: 0.00 AC: 0 AN: 14482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3362

East Asian (EAS) AF: 0.000211 AC: 1 AN: 4734

South Asian (SAS) AF: 0.000226 AC: 1 AN: 4434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64848

Other (OTH) AF: 0.000509 AC: 1 AN: 1966

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Beckwith-Wiedemann syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=196/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1380480846; hg19: chr11-2906078;