Genetic Variant CDKN1C:p.Ala194_Pro205dup (chr11-2884840-T-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP3

The NM_001122630.2(CDKN1C):c.581_616dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG(p.Ala194_Pro205dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D206D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

CDKN1C
NM_001122630.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.198

Publications

0 publications found

Variant links:

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

CDKN1C links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_001122630.2

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1C	NM_001122630.2	MANE Select	c.581_616dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala194_Pro205dup	conservative_inframe_insertion	Exon 2 of 4	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.614_649dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala205_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.614_649dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala205_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.581_616dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala194_Pro205dup	conservative_inframe_insertion	Exon 2 of 4	ENSP00000411257.2	P49918-2
CDKN1C	ENST00000414822.8	TSL:1	c.614_649dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala205_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.614_649dupCCCCGGCCCCGGCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala205_Pro216dup	conservative_inframe_insertion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.20

Splicing

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

Publications

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11-2884840-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG-TCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCGGGGGCCGGGGCCGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over