11-2884962-C-G

Position:

• chr11-2884962-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001122630.2(CDKN1C):​c.495G>C​(p.Ala165=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,050,826 control chromosomes in the GnomAD database, including 39 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. A165A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (30 hom.)
• Consequence: CDKN1C NM_001122630.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.489

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-2884962-C-G is Benign according to our data. Variant chr11-2884962-C-G is described in ClinVar as [Benign]. Clinvar id is 193041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884962-C-G is described in Lovd as [Benign]. Variant chr11-2884962-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BS2: High AC in GnomAd4 at 886 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.495G>C	p.Ala165=	synonymous_variant	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.495G>C	p.Ala165=	synonymous_variant	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 885 AN: 147142 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00631

Gnomad ASJ AF: 0.00206

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00506

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.00765

Gnomad OTH AF: 0.00348

GnomAD3 exomes AF: 0.0135 AC: 3 AN: 222 Hom.: 0 AF XY: 0.0156 AC XY: 2 AN XY: 128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00752 AC: 6796 AN: 903578 Hom.: 30 Cov.: 13 AF XY: 0.00765 AC XY: 3291 AN XY: 430106

Gnomad4 AFR exome AF: 0.000655

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00801

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.00771

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.00602 AC: 886 AN: 147248 Hom.: 9 Cov.: 32 AF XY: 0.00648 AC XY: 465 AN XY: 71806

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00637

Gnomad4 ASJ AF: 0.00206

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00506

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.00765

Gnomad4 OTH AF: 0.00344

Alfa AF: 0.00224 Hom.: 2

Bravo AF: 0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2020	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CDKN1C: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Beckwith-Wiedemann syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

CDKN1C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.1
DANN	Benign	0.70

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: rs533485167; hg19: chr11-2906192;