Genetic Variant CDKN1C:p.Pro179_Ala180del (chr11-2884917-GGCCGGA-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001122630.2(CDKN1C):c.534_539delTCCGGC(p.Pro179_Ala180del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 882,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A178A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 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:4

Conservation

PhyloP100: 0.0360

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
IMAGe syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884917-GGCCGGA-G is Benign according to our data. Variant chr11-2884917-GGCCGGA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236958.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000723 (104/143898) while in subpopulation SAS AF = 0.00211 (10/4744). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 104 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	UniProt
CDKN1C	NM_001122630.2	MANE Select	c.534_539delTCCGGC	p.Pro179_Ala180del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.567_572delTCCGGC	p.Pro190_Ala191del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.567_572delTCCGGC	p.Pro190_Ala191del	disruptive_inframe_deletion	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.534_539delTCCGGC	p.Pro179_Ala180del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
CDKN1C	ENST00000414822.8	TSL:1	c.567_572delTCCGGC	p.Pro190_Ala191del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.567_572delTCCGGC	p.Pro190_Ala191del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

104

AN:

143802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000957

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00179

Gnomad SAS

AF:

0.00211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000275

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.000381

AC:

281

AN:

738386

Hom.:

AF XY:

0.000390

AC XY:

136

AN XY:

348408

show subpopulations

African (AFR)

AF:

0.000783

AC:

AN:

12774

American (AMR)

AF:

0.000313

AC:

AN:

3196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6600

East Asian (EAS)

AF:

0.000523

AC:

AN:

7654

South Asian (SAS)

AF:

0.00130

AC:

AN:

14608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1710

European-Non Finnish (NFE)

AF:

0.000353

AC:

232

AN:

657216

Other (OTH)

AF:

0.000569

AC:

AN:

26364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000723

AC:

104

AN:

143898

Hom.:

Cov.:

AF XY:

0.000757

AC XY:

AN XY:

70026

show subpopulations

African (AFR)

AF:

0.000954

AC:

AN:

38792

American (AMR)

AF:

0.00204

AC:

AN:

14690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3364

East Asian (EAS)

AF:

0.00179

AC:

AN:

5018

South Asian (SAS)

AF:

0.00211

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000275

AC:

AN:

65488

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Beckwith-Wiedemann syndrome (1)

CDKN1C-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.036

Mutation Taster

=187/13

polymorphism

(source)

Splicing

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

Publications

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11-2884917-GGCCGGAGCCGGAGCCGGA-GGCCGGAGCCGGA

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