chr11-2884842-C-CGGGGCCGGGGCCGGGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP3BP6_Moderate

The NM_001122630.2(CDKN1C):c.597_614dupCGCCCCGGCCCCGGCCCC(p.Pro205_Asp206insAlaProAlaProAlaPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 986,300 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. P205P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0290

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: 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 -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, 40 uncertain in NM_001122630.2

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884842-C-CGGGGCCGGGGCCGGGGCG is Benign according to our data. Variant chr11-2884842-C-CGGGGCCGGGGCCGGGGCG is described in ClinVar as Likely_benign. ClinVar VariationId is 1155892.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.597_614dupCGCCCCGGCCCCGGCCCC	p.Pro205_Asp206insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	ENST00000440480.8	NP_001116102.1	P49918-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8 link	c.597_614dupCGCCCCGGCCCCGGCCCC	p.Pro205_Asp206insAlaProAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.00000698

AC:

AN:

143336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000203

AC:

AN:

986300

Hom.:

Cov.:

AF XY:

0.00000214

AC XY:

AN XY:

467268

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19396

American (AMR)

AF:

0.00

AC:

AN:

5508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10730

East Asian (EAS)

AF:

0.00

AC:

AN:

18748

South Asian (SAS)

AF:

0.00

AC:

AN:

21966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2446

European-Non Finnish (NFE)

AF:

0.00000234

AC:

AN:

855934

Other (OTH)

AF:

0.00

AC:

AN:

36506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000698

AC:

AN:

143336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39482

American (AMR)

AF:

0.00

AC:

AN:

14500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4754

South Asian (SAS)

AF:

0.00

AC:

AN:

4538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

65270

Other (OTH)

AF:

0.00

AC:

AN:

1980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome

Benign:1

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.029

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over