dbSNP rs878853637: CDKN1C:p.Ala190_Pro197del (chr11-2884866-CGGGGCCGGGGCCGGGGCCGGGGCT-C) – 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.567_590delAGCCCCGGCCCCGGCCCCGGCCCC(p.Ala190_Pro197del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 793,628 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P189P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 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:3

Conservation

PhyloP100: 1.91

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

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884866-CGGGGCCGGGGCCGGGGCCGGGGCT-C is Benign according to our data. Variant chr11-2884866-CGGGGCCGGGGCCGGGGCCGGGGCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236963.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000308 (41/133260) while in subpopulation NFE AF = 0.000519 (31/59782). AF 95% confidence interval is 0.000375. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 41 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.567_590delAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala190_Pro197del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.600_623delAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala201_Pro208del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.600_623delAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala201_Pro208del	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.567_590delAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala190_Pro197del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
CDKN1C	ENST00000414822.8	TSL:1	c.600_623delAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala201_Pro208del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.600_623delAGCCCCGGCCCCGGCCCCGGCCCC	p.Ala201_Pro208del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes

AF:

0.000308

AC:

AN:

133260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000216

Gnomad SAS

AF:

0.000465

Gnomad FIN

AF:

0.000128

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000519

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000903

AC:

596

AN:

660368

Hom.:

AF XY:

0.000888

AC XY:

276

AN XY:

310650

show subpopulations

African (AFR)

AF:

0.000235

AC:

AN:

12772

American (AMR)

AF:

0.00

AC:

AN:

1770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5206

East Asian (EAS)

AF:

0.000167

AC:

AN:

5982

South Asian (SAS)

AF:

0.000145

AC:

AN:

13834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1438

European-Non Finnish (NFE)

AF:

0.000954

AC:

565

AN:

592082

Other (OTH)

AF:

0.00110

AC:

AN:

22670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000308

AC:

AN:

133260

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

64878

show subpopulations

African (AFR)

AF:

0.000159

AC:

AN:

37814

American (AMR)

AF:

0.00

AC:

AN:

12832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3164

East Asian (EAS)

AF:

0.000216

AC:

AN:

4632

South Asian (SAS)

AF:

0.000465

AC:

AN:

4304

European-Finnish (FIN)

AF:

0.000128

AC:

AN:

7836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.000519

AC:

AN:

59782

Other (OTH)

AF:

0.00

AC:

AN:

1824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.000506

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Beckwith-Wiedemann syndrome (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=191/9

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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