rs771450542

Variant names:

• chr11-2884857-G-GGCCGGT
• rs771450542
• NM_001122630.2:c.599_600insACCGGC

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.599_600insACCGGC​(p.Ala200_Pro201insProAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,093,696 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. A200A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.397
• Publications: 2 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 NM_001122630.2
• BP6: Variant 11-2884857-G-GGCCGGT is Benign according to our data. Variant chr11-2884857-G-GGCCGGT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 236970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000163 (24/147004) while in subpopulation EAS AF = 0.00355 (18/5072). AF 95% confidence interval is 0.00229. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.599_600insACCGGC	p.Ala200_Pro201insProAla	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.632_633insACCGGC	p.Ala211_Pro212insProAla	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.632_633insACCGGC	p.Ala211_Pro212insProAla	disruptive_inframe_insertion	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.599_600insACCGGC	p.Ala200_Pro201insProAla	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.632_633insACCGGC	p.Ala211_Pro212insProAla	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.632_633insACCGGC	p.Ala211_Pro212insProAla	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes AF: 0.000163 AC: 24 AN: 146902 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00354

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000613 AC: 58 AN: 946692 Hom.: 1 Cov.: 18 AF XY: 0.0000470 AC XY: 21 AN XY: 447168

African (AFR) AF: 0.00 AC: 0 AN: 18528

American (AMR) AF: 0.00 AC: 0 AN: 4840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9678

East Asian (EAS) AF: 0.00230 AC: 39 AN: 16956

South Asian (SAS) AF: 0.000370 AC: 7 AN: 18904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2318

European-Non Finnish (NFE) AF: 0.00000726 AC: 6 AN: 826626

Other (OTH) AF: 0.000172 AC: 6 AN: 34868

GnomAD4 genome AF: 0.000163 AC: 24 AN: 147004 Hom.: 0 Cov.: 33 AF XY: 0.000251 AC XY: 18 AN XY: 71664

African (AFR) AF: 0.0000245 AC: 1 AN: 40848

American (AMR) AF: 0.00 AC: 0 AN: 14806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00355 AC: 18 AN: 5072

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66160

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs771450542; hg19: chr11-2906087; COSMIC: COSV105896267; COSMIC: COSV105896267;