11-2884866-CGGGGCCGGGGCCGGGGCCGGGGCT-CGGGGCCGGGGCCGGGGCCGGGGCTGGGGCCGGGGCCGGGGCCGGGGCT

Position:

• chr11-2884866-CGGGGCCGGGGCCGGGGCCGGGGCT-CGGGGCCGGGGCCGGGGCCGGGGCTGGGGCCGGGGCCGGGGCCGGGGCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP6_Moderate

The NM_001122630.2(CDKN1C):​c.590_591insAGCCCCGGCCCCGGCCCCGGCCCC​(p.Ala198_Pro205dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 133,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P197P) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000075 (0 hom., cov: 33)
• Consequence: CDKN1C NM_001122630.2 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.938

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001122630.2
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-2884866-C-CGGGGCCGGGGCCGGGGCCGGGGCT is Benign according to our data. Variant chr11-2884866-C-CGGGGCCGGGGCCGGGGCCGGGGCT is described in ClinVar as [Likely_benign]. Clinvar id is 524750.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.590_591insAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala198_Pro205dup	inframe_insertion	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.590_591insAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala198_Pro205dup	inframe_insertion	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.00000750 AC: 1 AN: 133262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 12

GnomAD4 genome AF: 0.00000750 AC: 1 AN: 133262 Hom.: 0 Cov.: 33 AF XY: 0.0000154 AC XY: 1 AN XY: 64880

Gnomad4 AFR AF: 0.0000264

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853637; hg19: chr11-2906096;