rs3741341

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001122630.2(CDKN1C):c.675G>A(p.Glu225Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,496,048 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 10 hom. )

Consequence

CDKN1C
NM_001122630.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.612

Publications

5 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 11-2884782-C-T is Benign according to our data. Variant chr11-2884782-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.612 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00225 (339/150912) while in subpopulation EAS AF = 0.0241 (123/5094). AF 95% confidence interval is 0.0207. There are 4 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 339 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.675G>A	p.Glu225Glu	synonymous_variant	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.675G>A	p.Glu225Glu	synonymous_variant	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

337

AN:

150808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00956

Gnomad ASJ

AF:

0.00318

Gnomad EAS

AF:

0.0241

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000396

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000325

Gnomad OTH

AF:

0.00578

GnomAD2 exomes

AF:

0.00389

AC:

601

AN:

154444

AF XY:

0.00300

show subpopulations

Gnomad AFR exome

AF:

0.000477

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.00193

Gnomad EAS exome

AF:

0.0212

Gnomad FIN exome

AF:

0.000237

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.00193

GnomAD4 exome

AF:

0.00129

AC:

1736

AN:

1345136

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

833

AN XY:

668542

show subpopulations

African (AFR)

AF:

0.000252

AC:

AN:

27824

American (AMR)

AF:

0.0120

AC:

423

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00279

AC:

AN:

22924

East Asian (EAS)

AF:

0.0268

AC:

809

AN:

30238

South Asian (SAS)

AF:

0.00133

AC:

104

AN:

78046

European-Finnish (FIN)

AF:

0.000488

AC:

AN:

34820

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4968

European-Non Finnish (NFE)

AF:

0.000205

AC:

217

AN:

1056764

Other (OTH)

AF:

0.00164

AC:

AN:

54366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00225

AC:

339

AN:

150912

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

188

AN XY:

73784

show subpopulations

African (AFR)

AF:

0.000436

AC:

AN:

41288

American (AMR)

AF:

0.00968

AC:

147

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00318

AC:

AN:

3460

East Asian (EAS)

AF:

0.0241

AC:

123

AN:

5094

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000396

AC:

AN:

10094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000325

AC:

AN:

67684

Other (OTH)

AF:

0.00572

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.00307

Asia WGS

AF:

0.0120

AC:

AN:

3404

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Beckwith-Wiedemann syndrome

Benign:1

Feb 04, 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

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

PhyloP100

0.61

Mutation Taster

=100/0

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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rs3741341

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