Genetic Variant CDKN1C:p.Val184Ala (chr11-2884906-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001122630.2(CDKN1C):c.551T>C(p.Val184Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 780,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V184G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.89

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044391274).

BP6

Variant 11-2884906-A-G is Benign according to our data. Variant chr11-2884906-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 454017.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000215 (27/125634) while in subpopulation SAS AF = 0.00213 (8/3756). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 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
CDKN1C	NM_001122630.2	MANE Select	c.551T>C	p.Val184Ala	missense	Exon 2 of 4	NP_001116102.1
CDKN1C	NM_000076.2		c.584T>C	p.Val195Ala	missense	Exon 1 of 3	NP_000067.1
CDKN1C	NM_001362474.2		c.584T>C	p.Val195Ala	missense	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.551T>C	p.Val184Ala	missense	Exon 2 of 4	ENSP00000411257.2
CDKN1C	ENST00000414822.8	TSL:1	c.584T>C	p.Val195Ala	missense	Exon 1 of 3	ENSP00000413720.3
CDKN1C	ENST00000430149.3	TSL:1	c.584T>C	p.Val195Ala	missense	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

125544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000245

Gnomad SAS

AF:

0.00213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000341

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

655226

Hom.:

Cov.:

AF XY:

0.0000486

AC XY:

AN XY:

308802

show subpopulations

African (AFR)

AF:

0.000245

AC:

AN:

12258

American (AMR)

AF:

0.00

AC:

AN:

2484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5500

East Asian (EAS)

AF:

0.00

AC:

AN:

5348

South Asian (SAS)

AF:

0.000381

AC:

AN:

13126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1456

European-Non Finnish (NFE)

AF:

0.0000222

AC:

AN:

585962

Other (OTH)

AF:

0.000217

AC:

AN:

23018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

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:

0.000215

AC:

AN:

125634

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

AN XY:

61248

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

33096

American (AMR)

AF:

0.00

AC:

AN:

13388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3052

East Asian (EAS)

AF:

0.000246

AC:

AN:

4072

South Asian (SAS)

AF:

0.00213

AC:

AN:

3756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.0000341

AC:

AN:

58720

Other (OTH)

AF:

0.00

AC:

AN:

1794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000337

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.584T>C (p.V195A) alteration is located in exon 1 (coding exon 1) of the CDKN1C gene. This alteration results from a T to C substitution at nucleotide position 584, causing the valine (V) at amino acid position 195 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

not provided

Uncertain:1

Sep 06, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Beckwith-Wiedemann syndrome

Benign:1

Oct 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome

Benign:1

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.22

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.032

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.71

M_CAP

Benign

0.011

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

-1.9

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.070

REVEL

Benign

0.010

Sift

Benign

0.094

Sift4G

Benign

1.0

Polyphen

0.012

Vest4

0.061

MutPred

0.25

Gain of relative solvent accessibility (P = 0.005)

MVP

0.76

MPC

1.5

ClinPred

0.047

GERP RS

-2.7

Varity_R

0.026

gMVP

0.076

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over