rs1060503860

Variant names:

• chr11-2884884-CGGGGCT-C
• rs1060503860
• NM_001122630.2:c.567_572delAGCCCC

Your query was ambiguous. Multiple possible variants found:

• chr11-2884884-CGGGGCT-C
• chr11-2884884-CGGGGCT-CGGGGCTGGGGCT

Variant summary

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

The ENST00000440480.8(CDKN1C):​c.567_572delAGCCCC​(p.Ala190_Pro191del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 878,418 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: CDKN1C ENST00000440480.8 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.31
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000440480.8
• BP6: Variant 11-2884884-CGGGGCT-C is Benign according to our data. Variant chr11-2884884-CGGGGCT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 524719.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 = 0.000406 (57/140384) while in subpopulation AFR AF = 0.00136 (52/38276). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000440480.8. 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.567_572delAGCCCC	p.Ala190_Pro191del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.600_605delAGCCCC	p.Ala201_Pro202del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.600_605delAGCCCC	p.Ala201_Pro202del	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.567_572delAGCCCC	p.Ala190_Pro191del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.600_605delAGCCCC	p.Ala201_Pro202del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.600_605delAGCCCC	p.Ala201_Pro202del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes AF: 0.000406 AC: 57 AN: 140320 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000624

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000908 AC: 67 AN: 738034 Hom.: 1 AF XY: 0.0000980 AC XY: 34 AN XY: 346912

African (AFR) AF: 0.00141 AC: 19 AN: 13460

American (AMR) AF: 0.00 AC: 0 AN: 2092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5620

East Asian (EAS) AF: 0.00 AC: 0 AN: 5336

South Asian (SAS) AF: 0.0000679 AC: 1 AN: 14720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1578

European-Non Finnish (NFE) AF: 0.0000692 AC: 46 AN: 664860

Other (OTH) AF: 0.0000395 AC: 1 AN: 25332

GnomAD4 genome AF: 0.000406 AC: 57 AN: 140384 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 23 AN XY: 68384

African (AFR) AF: 0.00136 AC: 52 AN: 38276

American (AMR) AF: 0.00 AC: 0 AN: 14038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 4728

South Asian (SAS) AF: 0.000223 AC: 1 AN: 4486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000624 AC: 4 AN: 64140

Other (OTH) AF: 0.00 AC: 0 AN: 1956

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=160/40	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1060503860; hg19: chr11-2906114;