rs747360016

Variant names:

• chr11-2884842-CGGGGCCGGGGCCGGGGCG-C
• rs747360016
• NM_001122630.2:c.597_614delCGCCCCGGCCCCGGCCCC

Your query was ambiguous. Multiple possible variants found:

• chr11-2884842-CGGGGCCGGGGCCGGGGCG-C
• chr11-2884842-CGGGGCCGGGGCCGGGGCG-CGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP3 BP6_Moderate BS1 BS2

The NM_000076.2(CDKN1C):​c.630_647delCGCCCCGGCCCCGGCCCC​(p.Ala211_Pro216del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,129,608 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. P210P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CDKN1C NM_000076.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.35
• 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: 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 -9 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_000076.2
• BP3: Nonframeshift variant in repetitive region in NM_000076.2
• BP6: Variant 11-2884842-CGGGGCCGGGGCCGGGGCG-C is Benign according to our data. Variant chr11-2884842-CGGGGCCGGGGCCGGGGCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 412856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000977 (14/143336) while in subpopulation SAS AF = 0.00022 (1/4538). AF 95% confidence interval is 0.0000494. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000076.2. 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.597_614delCGCCCCGGCCCCGGCCCC	p.Ala200_Pro205del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.630_647delCGCCCCGGCCCCGGCCCC	p.Ala211_Pro216del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.630_647delCGCCCCGGCCCCGGCCCC	p.Ala211_Pro216del	disruptive_inframe_deletion	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.597_614delCGCCCCGGCCCCGGCCCC	p.Ala200_Pro205del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.630_647delCGCCCCGGCCCCGGCCCC	p.Ala211_Pro216del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.630_647delCGCCCCGGCCCCGGCCCC	p.Ala211_Pro216del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes AF: 0.0000977 AC: 14 AN: 143336 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000690

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000210

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000107

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 1 AN: 7832 AF XY: 0.000188

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: 0.000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 126 AN: 986272 Hom.: 0 AF XY: 0.000139 AC XY: 65 AN XY: 467262

African (AFR) AF: 0.000103 AC: 2 AN: 19396

American (AMR) AF: 0.00 AC: 0 AN: 5508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10730

East Asian (EAS) AF: 0.000267 AC: 5 AN: 18748

South Asian (SAS) AF: 0.0000910 AC: 2 AN: 21966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2446

European-Non Finnish (NFE) AF: 0.000133 AC: 114 AN: 855908

Other (OTH) AF: 0.0000822 AC: 3 AN: 36504

GnomAD4 genome AF: 0.0000977 AC: 14 AN: 143336 Hom.: 0 Cov.: 33 AF XY: 0.000158 AC XY: 11 AN XY: 69806

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000101 AC: 4 AN: 39482

American (AMR) AF: 0.0000690 AC: 1 AN: 14500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.000210 AC: 1 AN: 4754

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000107 AC: 7 AN: 65270

Other (OTH) AF: 0.00 AC: 0 AN: 1980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000477588), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000319 AC: 1 AN: 3144

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Beckwith-Wiedemann syndrome (1)
-	-	1	CDKN1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=195/5	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs747360016; hg19: chr11-2906072;