11-2884906-A-G

Variant names:

• chr11-2884906-A-G
• rs1261515352
• NM_001122630.2:c.551T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001122630.2(CDKN1C):​c.551T>C​(p.Val184Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 780,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V184G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.89
• Publications: 0 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044391274).
• BP6: Variant 11-2884906-A-G is Benign according to our data. Variant chr11-2884906-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 454017.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000215 (27/125634) while in subpopulation SAS AF = 0.00213 (8/3756). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 27 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.551T>C	p.Val184Ala	missense	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.584T>C	p.Val195Ala	missense	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.584T>C	p.Val195Ala	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.551T>C	p.Val184Ala	missense	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.584T>C	p.Val195Ala	missense	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.584T>C	p.Val195Ala	missense	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 27 AN: 125544 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.00213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000341

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 26 AN: 655226 Hom.: 0 Cov.: 10 AF XY: 0.0000486 AC XY: 15 AN XY: 308802

African (AFR) AF: 0.000245 AC: 3 AN: 12258

American (AMR) AF: 0.00 AC: 0 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5500

East Asian (EAS) AF: 0.00 AC: 0 AN: 5348

South Asian (SAS) AF: 0.000381 AC: 5 AN: 13126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1456

European-Non Finnish (NFE) AF: 0.0000222 AC: 13 AN: 585962

Other (OTH) AF: 0.000217 AC: 5 AN: 23018

GnomAD4 genome AF: 0.000215 AC: 27 AN: 125634 Hom.: 0 Cov.: 32 AF XY: 0.000327 AC XY: 20 AN XY: 61248

African (AFR) AF: 0.000483 AC: 16 AN: 33096

American (AMR) AF: 0.00 AC: 0 AN: 13388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3052

East Asian (EAS) AF: 0.000246 AC: 1 AN: 4072

South Asian (SAS) AF: 0.00213 AC: 8 AN: 3756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000341 AC: 2 AN: 58720

Other (OTH) AF: 0.00 AC: 0 AN: 1794

Alfa AF: 0.000337 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Beckwith-Wiedemann syndrome (1)
-	-	1	Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.22
DANN	Benign	0.47
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.010
Sift	Benign	0.094	T
Sift4G	Benign	1.0	T
Polyphen		0.012	B
Vest4		0.061
MutPred		0.25		Gain of relative solvent accessibility (P = 0.005)
MVP		0.76
MPC		1.5
ClinPred		0.047	T
GERP RS		-2.7
Varity_R		0.026
gMVP		0.076
Mutation Taster		=96/4	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: rs1261515352; hg19: chr11-2906136;