11-2884935-AGCCGGGGCCGGGGCCGGG-AGCCGGG

Variant names:

• chr11-2884935-AGCCGGGGCCGGG-A
• rs878853629
• NM_001122630.2:c.510_521delCCCGGCCCCGGC

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.510_521delCCCGGCCCCGGC​(p.Pro171_Ala174del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 900,988 control chromosomes in the GnomAD database, including 8 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. A170A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (7 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.666
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001122630.2
• BP6: Variant 11-2884935-AGCCGGGGCCGGG-A is Benign according to our data. Variant chr11-2884935-AGCCGGGGCCGGG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 236955.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 = 0.00123 (167/135464) while in subpopulation NFE AF = 0.00219 (135/61712). AF 95% confidence interval is 0.00189. There are 1 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 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.510_521delCCCGGCCCCGGC	p.Pro171_Ala174del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.543_554delCCCGGCCCCGGC	p.Pro182_Ala185del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.543_554delCCCGGCCCCGGC	p.Pro182_Ala185del	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.510_521delCCCGGCCCCGGC	p.Pro171_Ala174del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.543_554delCCCGGCCCCGGC	p.Pro182_Ala185del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.543_554delCCCGGCCCCGGC	p.Pro182_Ala185del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 167 AN: 135374 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000215

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 122 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00202 AC: 1545 AN: 765524 Hom.: 7 AF XY: 0.00199 AC XY: 724 AN XY: 362936

African (AFR) AF: 0.000752 AC: 11 AN: 14626

American (AMR) AF: 0.000226 AC: 1 AN: 4428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8218

East Asian (EAS) AF: 0.00 AC: 0 AN: 12798

South Asian (SAS) AF: 0.000138 AC: 2 AN: 14462

European-Finnish (FIN) AF: 0.000153 AC: 2 AN: 13096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1918

European-Non Finnish (NFE) AF: 0.00224 AC: 1497 AN: 667230

Other (OTH) AF: 0.00111 AC: 32 AN: 28748

GnomAD4 genome AF: 0.00123 AC: 167 AN: 135464 Hom.: 1 Cov.: 32 AF XY: 0.00105 AC XY: 69 AN XY: 65858

African (AFR) AF: 0.000725 AC: 27 AN: 37220

American (AMR) AF: 0.000214 AC: 3 AN: 13988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3200

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4516

South Asian (SAS) AF: 0.00 AC: 0 AN: 4172

European-Finnish (FIN) AF: 0.000129 AC: 1 AN: 7746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00219 AC: 135 AN: 61712

Other (OTH) AF: 0.00 AC: 0 AN: 1868

Alfa AF: 0.000390 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 specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=200/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs878853629; hg19: chr11-2906165;