rs1416211722

Variant names:

• chr11-2884682-G-A
• rs1416211722
• NM_001122630.2:c.775C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2884682-G-A
• chr11-2884682-G-C
• chr11-2884682-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_001122630.2(CDKN1C):​c.775C>T​(p.Pro259Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000459 in 1,306,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P259T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.544
• Publications: 1 publications found

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]

CDKN1C Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• rhabdomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Beckwith-Wiedemann syndrome due to CDKN1C mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intrauterine growth restriction-short stature-early adult-onset diabetes syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Silver-Russell syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_001122630.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.24787521).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.775C>T	p.Pro259Ser	missense	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.808C>T	p.Pro270Ser	missense	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.808C>T	p.Pro270Ser	missense	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.775C>T	p.Pro259Ser	missense	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.808C>T	p.Pro270Ser	missense	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.808C>T	p.Pro270Ser	missense	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 126720 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000459 AC: 6 AN: 1306866 Hom.: 0 Cov.: 31 AF XY: 0.00000772 AC XY: 5 AN XY: 647954

African (AFR) AF: 0.00 AC: 0 AN: 26434

American (AMR) AF: 0.00 AC: 0 AN: 29460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20704

East Asian (EAS) AF: 0.00 AC: 0 AN: 29888

South Asian (SAS) AF: 0.00 AC: 0 AN: 72212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4330

European-Non Finnish (NFE) AF: 0.00000578 AC: 6 AN: 1038124

Other (OTH) AF: 0.00 AC: 0 AN: 52518

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.54
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Benign	0.041	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.11
MutPred		0.29		Gain of phosphorylation at P270 (P = 0.023)
MVP		0.50
MPC		1.3
ClinPred		0.36	T
GERP RS		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.13
gMVP		0.20
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs1416211722; hg19: chr11-2905912;