rs1060500177

chr11-2884957-A-Gchr11-2884957-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001122630.2(CDKN1C):c.500T>C(p.Leu167Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,000,036 control chromosomes in the GnomAD database, including 1 homozygotes. 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. L167A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (1 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.31

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045346975).
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.500T>C	p.Leu167Pro	missense_variant	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.500T>C	p.Leu167Pro	missense_variant	2/4	1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 7 AN: 132506 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000563

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: 0.0000819

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000576 AC: 50 AN: 867530 Hom.: 1 Cov.: 13 AF XY: 0.0000533 AC XY: 22 AN XY: 413118

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: 0.000363

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000566

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000528 AC: 7 AN: 132506 Hom.: 0 Cov.: 32 AF XY: 0.0000310 AC XY: 2 AN XY: 64542

Gnomad4 AFR AF: 0.0000563

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: 0.0000819

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.533T>C (p.L178P) alteration is located in exon 1 (coding exon 1) of the CDKN1C gene. This alteration results from a T to C substitution at nucleotide position 533, causing the leucine (L) at amino acid position 178 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.2
Dann	Benign	0.17
DEOGEN2	Benign	0.031	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0019	N
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.21	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.038
MutPred		0.28		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;
MVP		0.21
MPC		1.9
ClinPred		0.026	T
GERP RS		-3.3
Varity_R		0.039
gMVP		0.051

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: rs1060500177; hg19: chr11-2906187;