Genetic Variant CDKN1C:p.Pro199_Ala200insAlaProAlaPro (chr11-2884860-G-GGGGGCCGGGGCC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1BP3BP6_ModerateBS2

The NM_000076.2(CDKN1C):c.618_629dupGGCCCCGGCCCC(p.Pro210_Ala211insAlaProAlaPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 143,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P210P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN1C
NM_000076.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.73

Publications

5 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: 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

CDKN1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_000076.2

BP3

Nonframeshift variant in repetitive region in NM_000076.2

BP6

Variant 11-2884860-G-GGGGGCCGGGGCC is Benign according to our data. Variant chr11-2884860-G-GGGGGCCGGGGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 701029.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000076.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKN1C	NM_001122630.2	MANE Select	c.585_596dupGGCCCCGGCCCC	p.Pro199_Ala200insAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1
CDKN1C	NM_000076.2		c.618_629dupGGCCCCGGCCCC	p.Pro210_Ala211insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1
CDKN1C	NM_001362474.2		c.618_629dupGGCCCCGGCCCC	p.Pro210_Ala211insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.585_596dupGGCCCCGGCCCC	p.Pro199_Ala200insAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2
CDKN1C	ENST00000414822.8	TSL:1	c.618_629dupGGCCCCGGCCCC	p.Pro210_Ala211insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3
CDKN1C	ENST00000430149.3	TSL:1	c.618_629dupGGCCCCGGCCCC	p.Pro210_Ala211insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes

AF:

0.0000349

AC:

AN:

143230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000506

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:

0.0000463

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000341

AC:

AN:

879570

Hom.:

Cov.:

AF XY:

0.00000722

AC XY:

AN XY:

415602

show subpopulations

African (AFR)

AF:

0.0000585

AC:

AN:

17080

American (AMR)

AF:

0.00

AC:

AN:

4070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8740

East Asian (EAS)

AF:

0.00

AC:

AN:

15382

South Asian (SAS)

AF:

0.0000571

AC:

AN:

17524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2124

European-Non Finnish (NFE)

AF:

0.00000130

AC:

AN:

770300

Other (OTH)

AF:

0.00

AC:

AN:

32002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000349

AC:

AN:

143230

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

69764

show subpopulations

African (AFR)

AF:

0.0000506

AC:

AN:

39498

American (AMR)

AF:

0.00

AC:

AN:

14592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3372

East Asian (EAS)

AF:

0.00

AC:

AN:

4876

South Asian (SAS)

AF:

0.00

AC:

AN:

4580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000463

AC:

AN:

64768

Other (OTH)

AF:

0.00

AC:

AN:

2004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

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

1.7

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over