chr11-2884878-CGGGGCCGGGGCT-C

Variant names:

• chr11-2884878-CGGGGCCGGGGCT-C
• rs878853634
• NM_001122630.2:c.567_578delAGCCCCGGCCCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001122630.2(CDKN1C):​c.567_578delAGCCCCGGCCCC​(p.Ala190_Pro193del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 885,706 control chromosomes in the GnomAD database, including 4 homozygotes. 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. P189P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.900
• Publications: 4 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884878-CGGGGCCGGGGCT-C is Benign according to our data. Variant chr11-2884878-CGGGGCCGGGGCT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 236960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00393 (551/140330) while in subpopulation AFR AF = 0.011 (433/39450). AF 95% confidence interval is 0.0101. There are 1 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 551 AD gene.

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.567_578delAGCCCCGGCCCC	p.Ala190_Pro193del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.600_611delAGCCCCGGCCCC	p.Ala201_Pro204del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.600_611delAGCCCCGGCCCC	p.Ala201_Pro204del	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.567_578delAGCCCCGGCCCC	p.Ala190_Pro193del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.600_611delAGCCCCGGCCCC	p.Ala201_Pro204del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.600_611delAGCCCCGGCCCC	p.Ala201_Pro204del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

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

African (AFR) AF: 0.00901 AC: 128 AN: 14206

American (AMR) AF: 0.00 AC: 0 AN: 2310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5950

East Asian (EAS) AF: 0.00551 AC: 36 AN: 6530

South Asian (SAS) AF: 0.00321 AC: 49 AN: 15256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5616

Middle Eastern (MID) AF: 0.00122 AC: 2 AN: 1646

European-Non Finnish (NFE) AF: 0.0000913 AC: 61 AN: 668074

Other (OTH) AF: 0.00128 AC: 33 AN: 25788

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

African (AFR) AF: 0.0110 AC: 433 AN: 39450

American (AMR) AF: 0.00167 AC: 24 AN: 14346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3266

East Asian (EAS) AF: 0.0105 AC: 51 AN: 4856

South Asian (SAS) AF: 0.00484 AC: 22 AN: 4546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000160 AC: 10 AN: 62560

Other (OTH) AF: 0.00565 AC: 11 AN: 1948

Alfa AF: 0.0000615 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Beckwith-Wiedemann syndrome (2)
-	-	2	not provided (2)
-	-	1	CDKN1C-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=194/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs878853634; hg19: chr11-2906108;