Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1BP3BP6_Very_StrongBS1BS2

The NM_000076.2(CDKN1C):c.618_629delGGCCCCGGCCCC(p.Ala207_Pro210del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,022,736 control chromosomes in the GnomAD database, including 474 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P206P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 38 hom., cov: 32)

Exomes 𝑓: 0.024 ( 436 hom. )

Consequence

CDKN1C
NM_000076.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.91

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: Benign. The variant received -15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 36 uncertain in NM_000076.2

BP3

Nonframeshift variant in repetitive region in NM_000076.2

BP6

Variant 11-2884860-GGGGGCCGGGGCC-G is Benign according to our data. Variant chr11-2884860-GGGGGCCGGGGCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 236965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0184 (2642/143306) while in subpopulation NFE AF = 0.0297 (1926/64742). AF 95% confidence interval is 0.0286. There are 38 homozygotes in GnomAd4. There are 1227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2642 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_596delGGCCCCGGCCCC	p.Ala196_Pro199del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1
CDKN1C	NM_000076.2		c.618_629delGGCCCCGGCCCC	p.Ala207_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1
CDKN1C	NM_001362474.2		c.618_629delGGCCCCGGCCCC	p.Ala207_Pro210del	disruptive_inframe_deletion	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_596delGGCCCCGGCCCC	p.Ala196_Pro199del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2
CDKN1C	ENST00000414822.8	TSL:1	c.618_629delGGCCCCGGCCCC	p.Ala207_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3
CDKN1C	ENST00000430149.3	TSL:1	c.618_629delGGCCCCGGCCCC	p.Ala207_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2643

AN:

143212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00552

Gnomad AMI

AF:

0.0227

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0252

Gnomad EAS

AF:

0.000820

Gnomad SAS

AF:

0.00830

Gnomad FIN

AF:

0.00922

Gnomad MID

AF:

0.0296

Gnomad NFE

AF:

0.0297

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.00

AC:

AN:

804

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0244

AC:

21423

AN:

879430

Hom.:

436

AF XY:

0.0242

AC XY:

10041

AN XY:

415538

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

17080

American (AMR)

AF:

0.00565

AC:

AN:

4070

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

128

AN:

8740

East Asian (EAS)

AF:

0.000195

AC:

AN:

15382

South Asian (SAS)

AF:

0.00656

AC:

115

AN:

17524

European-Finnish (FIN)

AF:

0.00526

AC:

AN:

12348

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

2124

European-Non Finnish (NFE)

AF:

0.0264

AC:

20347

AN:

770166

Other (OTH)

AF:

0.0211

AC:

676

AN:

31996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

958

1915

2873

3830

4788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

984

1968

2952

3936

4920

<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:

0.0184

AC:

2642

AN:

143306

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1227

AN XY:

69866

show subpopulations

African (AFR)

AF:

0.00550

AC:

218

AN:

39606

American (AMR)

AF:

0.0154

AC:

225

AN:

14614

Ashkenazi Jewish (ASJ)

AF:

0.0252

AC:

AN:

3372

East Asian (EAS)

AF:

0.000823

AC:

AN:

4862

South Asian (SAS)

AF:

0.00831

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.00922

AC:

AN:

8354

Middle Eastern (MID)

AF:

0.0288

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0297

AC:

1926

AN:

64742

Other (OTH)

AF:

0.0203

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

123

246

368

491

614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Beckwith-Wiedemann syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=197/3

polymorphism

(source)

Splicing

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

Publications

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11-2884860-GGGGGCCGGGGCCGGGGCCGGGGCC-GGGGGCCGGGGCC

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over