rs754671425

Positions:

• chr11-2885047-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001122630.2(CDKN1C):​c.410C>A​(p.Pro137Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,187,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P137R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.977

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17457488).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.410C>A	p.Pro137Gln	missense_variant	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.410C>A	p.Pro137Gln	missense_variant	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000118 AC: 14 AN: 1187912 Hom.: 0 Cov.: 28 AF XY: 0.00000696 AC XY: 4 AN XY: 574604

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: 0.0000132

Gnomad4 OTH exome AF: 0.0000205

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000619 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	Baylor Genetics	Mar 12, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 148 of the CDKN1C protein (p.Pro148Gln). This variant is not present in population databases (gnomAD no frequency). 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: 454001). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.045	T;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.63	.;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.20	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.19
MutPred		0.22		Loss of glycosylation at P148 (P = 0.0181);Loss of glycosylation at P148 (P = 0.0181);.;
MVP		0.18
MPC		1.2
ClinPred		0.22	T
GERP RS		0.65
Varity_R		0.11
gMVP		0.28

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: rs754671425; hg19: chr11-2906277;