rs1554937506

Variant names:

• chr11-2884106-C-T
• rs1554937506
• NM_001122630.2:c.816G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4 BP6_Moderate BS2

The NM_001362475.2(CDKN1C):​c.284G>A​(p.Arg95His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000945 in 1,376,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: CDKN1C NM_001362475.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.631
• 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: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 11 uncertain in NM_001362475.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.32239535).
• BP6: Variant 11-2884106-C-T is Benign according to our data. Variant chr11-2884106-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 524718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001362475.2. 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.816G>A	p.Ala272Ala	synonymous	Exon 3 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_001362475.2		c.284G>A	p.Arg95His	missense	Exon 3 of 4	NP_001349404.1	A0A2R8YFP9
	CDKN1C	NM_000076.2		c.849G>A	p.Ala283Ala	synonymous	Exon 2 of 3	NP_000067.1	P49918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.816G>A	p.Ala272Ala	synonymous	Exon 3 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.849G>A	p.Ala283Ala	synonymous	Exon 2 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.849G>A	p.Ala283Ala	synonymous	Exon 2 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000945 AC: 13 AN: 1376224 Hom.: 0 Cov.: 32 AF XY: 0.0000118 AC XY: 8 AN XY: 677960

African (AFR) AF: 0.00 AC: 0 AN: 29298

American (AMR) AF: 0.00 AC: 0 AN: 34336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24650

East Asian (EAS) AF: 0.00 AC: 0 AN: 34038

South Asian (SAS) AF: 0.00 AC: 0 AN: 77530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45900

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

European-Non Finnish (NFE) AF: 0.0000122 AC: 13 AN: 1069310

Other (OTH) AF: 0.00 AC: 0 AN: 56832

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.051	T
PhyloP100		-0.63
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.26
Sift	Benign	0.080	T
Sift4G	Benign	0.32	T
Polyphen		0.99	D
Vest4		0.17
MutPred		0.26		Loss of loop (P = 0.0075)
MVP		0.81
ClinPred		0.31	T
GERP RS		0.93
Mutation Taster		=89/11	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: rs1554937506; hg19: chr11-2905336;