rs387907225

Positions:

• chr11-2884670-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001122630.2(CDKN1C):​c.787G>A​(p.Asp263Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,232,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.556

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001122630.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 11-2884670-C-T is Pathogenic according to our data. Variant chr11-2884670-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 35531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.787G>A	p.Asp263Asn	missense_variant, splice_region_variant	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.787G>A	p.Asp263Asn	missense_variant, splice_region_variant	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1232274 Hom.: 0 Cov.: 29 AF XY: 0.00000165 AC XY: 1 AN XY: 607320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beckwith-Wiedemann syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

ClinVar contains an entry for this variant (Variation ID: 35531). This missense change has been observed in individual(s) with IMAGe syndrome (PMID: 22634751, 24313804). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 274 of the CDKN1C protein (p.Asp274Asn). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CDKN1C function (PMID: 24098681). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2022

The c.820G>A (p.D274N) alteration is located in exon 1 (coding exon 1) of the CDKN1C gene. This alteration results from a G to A substitution at nucleotide position 820, causing the aspartic acid (D) at amino acid position 274 to be replaced by an asparagine (N)._x000D_ _x000D_ Based on the available evidence, the CDKN1C c.820G>A (p.D274N) alteration is classified as pathogenic for IMAGE syndrome; however, this variant is unlikely to be causative of Beckwith-Wiedemann syndrome. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed in multiple unrelated individuals with IMAGE syndrome and has been reported as de novo and maternally inherited (Arboleda, 2012; Kato, 2014; Amano, 2017; Homma, 2019; Bolomiti, 2021). This amino acid position is well conserved in available vertebrate species with limited sequence alignment. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional assays modestly suggest that protein stability is increased, but additional evidence is needed to confirm these data (Hamajima, 2013). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

IMAGe syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 27, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.
Eigen	Benign	0.053
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.61	.;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.76
MutPred		0.24		Gain of MoRF binding (P = 0.052);Gain of MoRF binding (P = 0.052);.;
MVP		0.80
MPC		1.2
ClinPred		0.86	D
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.43
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907225; hg19: chr11-2905900;