Genetic Variant CDKN1C:p.Ala198_Pro199del (chr11-2884860-GGGGGCC-G) – ACMG Classification: Benign (-15 pts)

Variant summary

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

The NM_000076.2(CDKN1C):c.624_629delGGCCCC(p.Ala209_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 0.00153 in 1,022,866 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P208P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0064 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

CDKN1C
NM_000076.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.90

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:

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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 1 benign, 36 uncertain in NM_000076.2

BP3

Nonframeshift variant in repetitive region in NM_000076.2

BP6

Variant 11-2884860-GGGGGCC-G is Benign according to our data. Variant chr11-2884860-GGGGGCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 236967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00636 (912/143316) while in subpopulation AMR AF = 0.0411 (600/14612). AF 95% confidence interval is 0.0383. There are 20 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 912 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.591_596delGGCCCC	p.Ala198_Pro199del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1
CDKN1C	NM_000076.2		c.624_629delGGCCCC	p.Ala209_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1
CDKN1C	NM_001362474.2		c.624_629delGGCCCC	p.Ala209_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.591_596delGGCCCC	p.Ala198_Pro199del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2
CDKN1C	ENST00000414822.8	TSL:1	c.624_629delGGCCCC	p.Ala209_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3
CDKN1C	ENST00000430149.3	TSL:1	c.624_629delGGCCCC	p.Ala209_Pro210del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

900

AN:

143222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0404

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000205

Gnomad SAS

AF:

0.00306

Gnomad FIN

AF:

0.000239

Gnomad MID

AF:

0.00987

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.00948

GnomAD4 exome

AF:

0.000739

AC:

650

AN:

879550

Hom.:

AF XY:

0.000729

AC XY:

303

AN XY:

415590

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

17080

American (AMR)

AF:

0.0143

AC:

AN:

4070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8740

East Asian (EAS)

AF:

0.00

AC:

AN:

15382

South Asian (SAS)

AF:

0.00200

AC:

AN:

17524

European-Finnish (FIN)

AF:

0.000162

AC:

AN:

12348

Middle Eastern (MID)

AF:

0.00377

AC:

AN:

2124

European-Non Finnish (NFE)

AF:

0.000641

AC:

494

AN:

770280

Other (OTH)

AF:

0.00106

AC:

AN:

32002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00636

AC:

912

AN:

143316

Hom.:

Cov.:

AF XY:

0.00686

AC XY:

479

AN XY:

69866

show subpopulations

African (AFR)

AF:

0.00437

AC:

173

AN:

39606

American (AMR)

AF:

0.0411

AC:

600

AN:

14612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3372

East Asian (EAS)

AF:

0.000206

AC:

AN:

4862

South Asian (SAS)

AF:

0.00284

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.000239

AC:

AN:

8354

Middle Eastern (MID)

AF:

0.00719

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00158

AC:

102

AN:

64754

Other (OTH)

AF:

0.00940

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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 as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Beckwith-Wiedemann syndrome (2)

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=160/40

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over