NM_001122630.2:c.479_490delCTCCGGTCGCGG

Variant names:

• chr11-2884966-ACCGCGACCGGAG-A
• rs565544512
• NM_001122630.2:c.479_490delCTCCGGTCGCGG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001122630.2(CDKN1C):​c.479_490delCTCCGGTCGCGG​(p.Ala160_Ala163del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 980,206 control chromosomes in the GnomAD database, including 29,470 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. A160A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (3243 hom., cov: 25)
  • Exomes 𝑓: 0.23 (26227 hom.)
• Consequence: CDKN1C NM_001122630.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.593
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), 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 11-2884966-ACCGCGACCGGAG-A is Benign according to our data. Variant chr11-2884966-ACCGCGACCGGAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

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.479_490delCTCCGGTCGCGG	p.Ala160_Ala163del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.512_523delCTCCGGTCGCGG	p.Ala171_Ala174del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.512_523delCTCCGGTCGCGG	p.Ala171_Ala174del	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.479_490delCTCCGGTCGCGG	p.Ala160_Ala163del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.512_523delCTCCGGTCGCGG	p.Ala171_Ala174del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.512_523delCTCCGGTCGCGG	p.Ala171_Ala174del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 28094 AN: 136298 Hom.: 3242 Cov.: 25

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.282 AC: 62 AN: 220 AF XY: 0.333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.234 AC: 197281 AN: 843828 Hom.: 26227 AF XY: 0.236 AC XY: 95074 AN XY: 403256

African (AFR) AF: 0.0674 AC: 1204 AN: 17856

American (AMR) AF: 0.234 AC: 1568 AN: 6704

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 3224 AN: 11040

East Asian (EAS) AF: 0.0862 AC: 1841 AN: 21348

South Asian (SAS) AF: 0.172 AC: 2812 AN: 16370

European-Finnish (FIN) AF: 0.175 AC: 3476 AN: 19850

Middle Eastern (MID) AF: 0.253 AC: 592 AN: 2344

European-Non Finnish (NFE) AF: 0.245 AC: 174902 AN: 714110

Other (OTH) AF: 0.224 AC: 7662 AN: 34206

GnomAD4 genome AF: 0.206 AC: 28081 AN: 136378 Hom.: 3243 Cov.: 25 AF XY: 0.201 AC XY: 13336 AN XY: 66300

African (AFR) AF: 0.0888 AC: 3162 AN: 35590

American (AMR) AF: 0.224 AC: 3188 AN: 14242

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1020 AN: 3300

East Asian (EAS) AF: 0.104 AC: 462 AN: 4446

South Asian (SAS) AF: 0.189 AC: 816 AN: 4326

European-Finnish (FIN) AF: 0.178 AC: 1433 AN: 8060

Middle Eastern (MID) AF: 0.270 AC: 66 AN: 244

European-Non Finnish (NFE) AF: 0.273 AC: 17323 AN: 63434

Other (OTH) AF: 0.233 AC: 444 AN: 1906

Alfa AF: 0.0616 Hom.: 79

Asia WGS AF: 0.103 AC: 320 AN: 3080

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Beckwith-Wiedemann syndrome (2)
-	-	2	not provided (2)
-	-	1	CDKN1C-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
Mutation Taster		=198/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs565544512; hg19: chr11-2906196; COSMIC: COSV57832997; COSMIC: COSV57832997;