Genetic Variant NM_001122630.2:c.591_596dupGGCCCC (chr11-2884860-G-GGGGGCC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM1BP3BP6BS1BS2

The NM_001122630.2(CDKN1C):c.591_596dupGGCCCC(p.Pro199_Ala200insAlaPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 143,322 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. P199P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.73

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: 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 -8 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, 38 uncertain in NM_001122630.2

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884860-G-GGGGGCC is Benign according to our data. Variant chr11-2884860-G-GGGGGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236968.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00097 (139/143322) while in subpopulation SAS AF = 0.00525 (24/4574). AF 95% confidence interval is 0.00362. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 139 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.591_596dupGGCCCC	p.Pro199_Ala200insAlaPro	disruptive_inframe_insertion	Exon 2 of 4	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.624_629dupGGCCCC	p.Pro210_Ala211insAlaPro	disruptive_inframe_insertion	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.624_629dupGGCCCC	p.Pro210_Ala211insAlaPro	disruptive_inframe_insertion	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.591_596dupGGCCCC	p.Pro199_Ala200insAlaPro	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000411257.2	P49918-2
CDKN1C	ENST00000414822.8	TSL:1	c.624_629dupGGCCCC	p.Pro210_Ala211insAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.624_629dupGGCCCC	p.Pro210_Ala211insAlaPro	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes

AF:

0.000970

AC:

139

AN:

143228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000480

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00144

Gnomad SAS

AF:

0.00524

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000556

Gnomad OTH

AF:

0.00200

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000156

AC:

137

AN:

879568

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

415600

show subpopulations

African (AFR)

AF:

0.000351

AC:

AN:

17080

American (AMR)

AF:

0.00

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:

0.00103

AC:

AN:

17524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2124

European-Non Finnish (NFE)

AF:

0.000136

AC:

105

AN:

770298

Other (OTH)

AF:

0.000250

AC:

AN:

32002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000970

AC:

139

AN:

143322

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

69870

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

39604

American (AMR)

AF:

0.000479

AC:

AN:

14614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3372

East Asian (EAS)

AF:

0.00144

AC:

AN:

4862

South Asian (SAS)

AF:

0.00525

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000556

AC:

AN:

64760

Other (OTH)

AF:

0.00198

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Beckwith-Wiedemann syndrome (2)

CDKN1C-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=81/19

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