rs1224283171

Variant names:

• chr11-2885267-C-T
• rs1224283171
• NM_001122630.2:c.190G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001122630.2(CDKN1C):​c.190G>A​(p.Gly64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.60

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.190G>A	p.Gly64Arg	missense_variant	Exon 2 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.190G>A	p.Gly64Arg	missense_variant	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425046 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000499

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beckwith-Wiedemann syndrome Uncertain:1

Nov 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 75 of the CDKN1C protein (p.Gly75Arg). 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: 453992). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDKN1C protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.83	.;T;T;.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D;D;D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Uncertain	0.010	D;D;D;D;.
Polyphen		1.0	D;D;.;D;.
Vest4		0.39
MutPred		0.84		Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;.;.;
MVP		0.92
MPC		2.7
ClinPred		0.94	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.79
gMVP		0.96

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: rs1224283171; hg19: chr11-2906497;