rs781340171

chr11-2884688-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001122630.2(CDKN1C):c.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,465,436 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S257F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.407

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001122630.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.15285984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.769T>A	p.Ser257Thr	missense_variant	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.769T>A	p.Ser257Thr	missense_variant	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146342 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000147 AC: 2 AN: 136466 Hom.: 0 AF XY: 0.0000253 AC XY: 2 AN XY: 79004

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000314

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000986 AC: 13 AN: 1319094 Hom.: 0 Cov.: 31 AF XY: 0.0000107 AC XY: 7 AN XY: 654918

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000124

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146342 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 1 AN XY: 71442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000300

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000183 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 268 of the CDKN1C protein (p.Ser268Thr). This variant is present in population databases (rs781340171, gnomAD 0.004%). 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: 524702). 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	Oct 19, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.054	T;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.031	N
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.036	D;D;D
Sift4G	Benign	0.61	T;T;T
Polyphen		0.023	B;B;.
Vest4		0.097
MutPred		0.14		Loss of phosphorylation at S268 (P = 0.0621);Loss of phosphorylation at S268 (P = 0.0621);.;
MVP		0.53
MPC		1.4
ClinPred		0.036	T
GERP RS		-0.52
Varity_R		0.13
gMVP		0.15

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: rs781340171; hg19: chr11-2905918;