NM_001122630.2:c.553G>C

Variant names:

• chr11-2884904-C-G
• rs1281835164
• NM_001122630.2:c.553G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001122630.2(CDKN1C):​c.553G>C​(p.Ala185Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 134,462 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. A185L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -1.18
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06399709).
• BP6: Variant 11-2884904-C-G is Benign according to our data. Variant chr11-2884904-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 524686.

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.553G>C	p.Ala185Pro	missense	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.586G>C	p.Ala196Pro	missense	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.586G>C	p.Ala196Pro	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.553G>C	p.Ala185Pro	missense	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.586G>C	p.Ala196Pro	missense	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.586G>C	p.Ala196Pro	missense	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.0000149 AC: 2 AN: 134462 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000162

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000424 AC: 3 AN: 708232 Hom.: 0 Cov.: 10 AF XY: 0.00000300 AC XY: 1 AN XY: 333274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13184

American (AMR) AF: 0.00 AC: 0 AN: 2436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5648

East Asian (EAS) AF: 0.00 AC: 0 AN: 5268

South Asian (SAS) AF: 0.00 AC: 0 AN: 14176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1512

European-Non Finnish (NFE) AF: 0.00000472 AC: 3 AN: 635714

Other (OTH) AF: 0.00 AC: 0 AN: 24630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0561929), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000149 AC: 2 AN: 134462 Hom.: 0 Cov.: 32 AF XY: 0.0000153 AC XY: 1 AN XY: 65262

African (AFR) AF: 0.00 AC: 0 AN: 36212

American (AMR) AF: 0.00 AC: 0 AN: 14018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3208

East Asian (EAS) AF: 0.000220 AC: 1 AN: 4542

South Asian (SAS) AF: 0.00 AC: 0 AN: 4238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000162 AC: 1 AN: 61654

Other (OTH) AF: 0.00 AC: 0 AN: 1880

Alfa AF: 0.00 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.96
DANN	Benign	0.61
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.014
Sift	Benign	0.22	T
Sift4G	Benign	1.0	T
Polyphen		0.030	B
Vest4		0.092
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.39
MPC		1.6
ClinPred		0.043	T
GERP RS		-2.7
Varity_R		0.050
gMVP		0.070
Mutation Taster		=94/6	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: rs1281835164; hg19: chr11-2906134;