Genetic Variant ENST00000414822.8:c.12G>C (chr11-2885478-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The ENST00000414822.8(CDKN1C):c.12G>C(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,543,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDKN1C
ENST00000414822.8 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0980

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

new If you want to explore the variant's impact on the transcript ENST00000414822.8, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 11-2885478-C-G is Benign according to our data. Variant chr11-2885478-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 453989.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.098 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000414822.8. 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.-10-12G>C		intron	N/A	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.12G>C	p.Ala4Ala	synonymous	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.12G>C	p.Ala4Ala	synonymous	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1C	ENST00000414822.8	TSL:1	c.12G>C	p.Ala4Ala	synonymous	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.12G>C	p.Ala4Ala	synonymous	Exon 1 of 3	ENSP00000411552.2	P49918-1
CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.-10-12G>C		intron	N/A	ENSP00000411257.2	P49918-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000684

AC:

AN:

146190

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000894

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1391644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31602

American (AMR)

AF:

0.00

AC:

AN:

35720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.0000559

AC:

AN:

35770

South Asian (SAS)

AF:

0.00

AC:

AN:

79260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078986

Other (OTH)

AF:

0.00

AC:

AN:

57970

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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: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

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.098

PromoterAI

0.018

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over