rs878853642

Positions:

• chr11-2884720-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122630.2(CDKN1C):​c.737C>G​(p.Ala246Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,353,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.51

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18224892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.737C>G	p.Ala246Gly	missense_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.737C>G	p.Ala246Gly	missense_variant	2/4	1	NM_001122630.2	ENSP00000411257	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000628 AC: 1 AN: 159146 Hom.: 0 AF XY: 0.0000109 AC XY: 1 AN XY: 91754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1353748 Hom.: 0 Cov.: 31 AF XY: 0.00000297 AC XY: 2 AN XY: 673578

Gnomad4 AFR exome AF: 0.0000362

Gnomad4 AMR exome AF: 0.0000289

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 257 of the CDKN1C protein (p.Ala257Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CDKN1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 236975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDKN1C protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 05, 2023	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.40	.;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.016	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.59	P;P;.
Vest4		0.18
MutPred		0.33		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;
MVP		0.37
MPC		1.3
ClinPred		0.083	T
GERP RS		1.9
Varity_R		0.17
gMVP		0.067

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: rs878853642; hg19: chr11-2905950;