rs778468310

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1BP3BP6_ModerateBS1BS2

The NM_001122630.2(CDKN1C):c.593_616delCCCCCGCCCCGGCCCCGGCCCCGG(p.Ala198_Pro205del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000585 in 1,129,160 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. A198A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.949

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: 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 -9 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, 37 uncertain in NM_001122630.2

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884840-TCCGGGGCCGGGGCCGGGGCGGGGG-T is Benign according to our data. Variant chr11-2884840-TCCGGGGCCGGGGCCGGGGCGGGGG-T is described in ClinVar as Benign. ClinVar VariationId is 454020.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000624 (62/994040) while in subpopulation EAS AF = 0.000112 (2/17794). AF 95% confidence interval is 0.0000517. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.593_616delCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala198_Pro205del	disruptive_inframe_deletion	Exon 2 of 4	ENST00000440480.8	NP_001116102.1	P49918-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8 link	c.593_616delCCCCCGCCCCGGCCCCGGCCCCGG	p.Ala198_Pro205del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.0000296

AC:

AN:

135120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000826

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000159

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000624

AC:

AN:

994040

Hom.:

AF XY:

0.0000651

AC XY:

AN XY:

475914

show subpopulations

African (AFR)

AF:

0.0000518

AC:

AN:

19300

American (AMR)

AF:

0.00

AC:

AN:

6496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12022

East Asian (EAS)

AF:

0.000112

AC:

AN:

17794

South Asian (SAS)

AF:

0.00

AC:

AN:

29908

European-Finnish (FIN)

AF:

0.000139

AC:

AN:

14368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2614

European-Non Finnish (NFE)

AF:

0.0000655

AC:

AN:

855012

Other (OTH)

AF:

0.0000274

AC:

AN:

36526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000296

AC:

AN:

135120

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

65772

show subpopulations

African (AFR)

AF:

0.0000826

AC:

AN:

36340

American (AMR)

AF:

0.00

AC:

AN:

13842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3296

East Asian (EAS)

AF:

0.00

AC:

AN:

4188

South Asian (SAS)

AF:

0.00

AC:

AN:

3958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.0000159

AC:

AN:

63076

Other (OTH)

AF:

0.00

AC:

AN:

1874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.95

Mutation Taster

=194/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over