dbSNP rs565544512: CDKN1C:p.Ala156_Ala163del (chr11-2884966-ACCGCGACCGGAGCCGCGACCGGAG-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_001122630.2(CDKN1C):c.467_490delCTCCGGTCGCGGCTCCGGTCGCGG(p.Ala156_Ala163del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 981,980 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000022 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.593

Publications

8 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 -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884966-ACCGCGACCGGAGCCGCGACCGGAG-A is Benign according to our data. Variant chr11-2884966-ACCGCGACCGGAGCCGCGACCGGAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 454006.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000022 (3/136442) while in subpopulation SAS AF = 0.000461 (2/4334). AF 95% confidence interval is 0.0000816. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 19 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.467_490delCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala156_Ala163del	disruptive_inframe_deletion	Exon 2 of 4	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.500_523delCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala167_Ala174del	disruptive_inframe_deletion	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.500_523delCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala167_Ala174del	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.467_490delCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala156_Ala163del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000411257.2	P49918-2
CDKN1C	ENST00000414822.8	TSL:1	c.500_523delCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala167_Ala174del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.500_523delCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala167_Ala174del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes

AF:

0.0000220

AC:

AN:

136442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000703

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000461

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000225

AC:

AN:

845538

Hom.:

AF XY:

0.0000173

AC XY:

AN XY:

404056

show subpopulations

African (AFR)

AF:

0.0000560

AC:

AN:

17868

American (AMR)

AF:

0.00

AC:

AN:

6718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11060

East Asian (EAS)

AF:

0.0000936

AC:

AN:

21360

South Asian (SAS)

AF:

0.0000610

AC:

AN:

16386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2344

European-Non Finnish (NFE)

AF:

0.0000168

AC:

AN:

715682

Other (OTH)

AF:

0.0000876

AC:

AN:

34264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.0000220

AC:

AN:

136442

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

66298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35524

American (AMR)

AF:

0.0000703

AC:

AN:

14234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3302

East Asian (EAS)

AF:

0.00

AC:

AN:

4460

South Asian (SAS)

AF:

0.000461

AC:

AN:

4334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63524

Other (OTH)

AF:

0.00

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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 as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.59

Mutation Taster

=184/16

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