rs529326848

Positions:

• chr11-2884890-T-C
• chr11-2884890-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000440480.8(CDKN1C):​c.567A>G​(p.Pro189=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 741,352 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P189P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (162 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (44 hom.)
• Consequence: CDKN1C ENST00000440480.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -8.37

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-2884890-T-C is Benign according to our data. Variant chr11-2884890-T-C is described in ClinVar as [Benign]. Clinvar id is 236964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884890-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.567A>G	p.Pro189=	synonymous_variant	2/4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.567A>G	p.Pro189=	synonymous_variant	2/4	1	NM_001122630.2	ENSP00000411257	A2

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 3880 AN: 107736 Hom.: 161 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0289

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.00465

Gnomad EAS AF: 0.00111

Gnomad SAS AF: 0.00924

Gnomad FIN AF: 0.00135

Gnomad MID AF: 0.0400

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.00416 AC: 2637 AN: 633540 Hom.: 44 Cov.: 9 AF XY: 0.00393 AC XY: 1172 AN XY: 298128

Gnomad4 AFR exome AF: 0.0897

Gnomad4 AMR exome AF: 0.00712

Gnomad4 ASJ exome AF: 0.00385

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.000664

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.0361 AC: 3888 AN: 107812 Hom.: 162 Cov.: 31 AF XY: 0.0345 AC XY: 1829 AN XY: 53056

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.00465

Gnomad4 EAS AF: 0.00112

Gnomad4 SAS AF: 0.00955

Gnomad4 FIN AF: 0.00135

Gnomad4 NFE AF: 0.00320

Gnomad4 OTH AF: 0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2017	- -

Beckwith-Wiedemann syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.0
DANN	Benign	0.46

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

LitVar

Other links and lift over

dbSNP: rs529326848; hg19: chr11-2906120;