Genetic Variant CDKN1C:p.Pro183_Val184insAlaProAlaPro (chr11-2884908-T-TGGAGCCGGGGCC) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_001122630.2(CDKN1C):c.537_548dupGGCCCCGGCTCC(p.Pro183_Val184insAlaProAlaPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 770,016 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. P183P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.623

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884908-T-TGGAGCCGGGGCC is Benign according to our data. Variant chr11-2884908-T-TGGAGCCGGGGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 404239.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000049 (32/653050) while in subpopulation AFR AF = 0.0000816 (1/12252). AF 95% confidence interval is 0.0000381. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 32 AD gene.

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
CDKN1C	NM_001122630.2	MANE Select	c.537_548dupGGCCCCGGCTCC	p.Pro183_Val184insAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1
CDKN1C	NM_000076.2		c.570_581dupGGCCCCGGCTCC	p.Pro194_Val195insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1
CDKN1C	NM_001362474.2		c.570_581dupGGCCCCGGCTCC	p.Pro194_Val195insAlaProAlaPro	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.537_548dupGGCCCCGGCTCC	p.Pro183_Val184insAlaProAlaPro	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2
CDKN1C	ENST00000414822.8	TSL:1	c.570_581dupGGCCCCGGCTCC	p.Pro194_Val195insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3
CDKN1C	ENST00000430149.3	TSL:1	c.570_581dupGGCCCCGGCTCC	p.Pro194_Val195insAlaProAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes

AF:

0.0000342

AC:

AN:

116966

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:

0.0000727

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000490

AC:

AN:

653050

Hom.:

Cov.:

AF XY:

0.0000519

AC XY:

AN XY:

308004

show subpopulations

African (AFR)

AF:

0.0000816

AC:

AN:

12252

American (AMR)

AF:

0.00

AC:

AN:

2548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5534

East Asian (EAS)

AF:

0.00

AC:

AN:

5630

South Asian (SAS)

AF:

0.00

AC:

AN:

13018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1494

European-Non Finnish (NFE)

AF:

0.0000532

AC:

AN:

583094

Other (OTH)

AF:

0.00

AC:

AN:

23122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

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:

0.0000342

AC:

AN:

116966

Hom.:

Cov.:

AF XY:

0.0000350

AC XY:

AN XY:

57200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30392

American (AMR)

AF:

0.00

AC:

AN:

12568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2890

East Asian (EAS)

AF:

0.00

AC:

AN:

3860

South Asian (SAS)

AF:

0.00

AC:

AN:

3540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.0000727

AC:

AN:

54984

Other (OTH)

AF:

0.00

AC:

AN:

1612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome

Benign:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.62

Mutation Taster

=82/18

polymorphism

(source)

Splicing

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

Publications

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11-2884908-TGGAGCCGGGGCC-TGGAGCCGGGGCCGGAGCCGGGGCC

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over