chr11-2884890-TGGGGCCGGGGCC-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_001122630.2(CDKN1C):c.555_566delGGCCCCGGCCCC(p.Ala186_Pro189del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000674 in 741,430 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A185A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.36

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 -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884890-TGGGGCCGGGGCC-T is Benign according to our data. Variant chr11-2884890-TGGGGCCGGGGCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1591652.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.555_566delGGCCCCGGCCCC	p.Ala186_Pro189del	disruptive_inframe_deletion	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.555_566delGGCCCCGGCCCC	p.Ala186_Pro189del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.0000186

AC:

AN:

107750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000870

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:

0.0000204

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000473

AC:

AN:

633604

Hom.:

AF XY:

0.00000671

AC XY:

AN XY:

298166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11656

American (AMR)

AF:

0.00

AC:

AN:

1966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4932

East Asian (EAS)

AF:

0.00

AC:

AN:

4346

South Asian (SAS)

AF:

0.00

AC:

AN:

12780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1394

European-Non Finnish (NFE)

AF:

0.00000526

AC:

AN:

570030

Other (OTH)

AF:

0.00

AC:

AN:

21982

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

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:

0.0000185

AC:

AN:

107826

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

53064

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

29770

American (AMR)

AF:

0.0000870

AC:

AN:

11492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2582

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

3246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

144

European-Non Finnish (NFE)

AF:

0.0000204

AC:

AN:

49024

Other (OTH)

AF:

0.00

AC:

AN:

1474

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome

Uncertain:1

Jan 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Beckwith-Wiedemann syndrome

Benign:1

Aug 06, 2024

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

2.4

Mutation Taster

=195/5

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