11-2885046-C-T

Variant names:

• chr11-2885046-C-T
• rs878853625
• NM_001122630.2:c.411G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001122630.2(CDKN1C):​c.411G>A​(p.Pro137Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,336,348 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P137P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: CDKN1C NM_001122630.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.707
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-2885046-C-T is Benign according to our data. Variant chr11-2885046-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236951.
• BP7: Synonymous conserved (PhyloP=-0.707 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000199 (30/150798) while in subpopulation NFE AF = 0.00034 (23/67576). AF 95% confidence interval is 0.000232. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 30 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.411G>A	p.Pro137Pro	synonymous	Exon 2 of 4	NP_001116102.1	P49918-2
	CDKN1C	NM_000076.2		c.444G>A	p.Pro148Pro	synonymous	Exon 1 of 3	NP_000067.1	P49918-1
	CDKN1C	NM_001362474.2		c.444G>A	p.Pro148Pro	synonymous	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.411G>A	p.Pro137Pro	synonymous	Exon 2 of 4	ENSP00000411257.2	P49918-2
	CDKN1C	ENST00000414822.8	TSL:1	c.444G>A	p.Pro148Pro	synonymous	Exon 1 of 3	ENSP00000413720.3	P49918-1
	CDKN1C	ENST00000430149.3	TSL:1	c.444G>A	p.Pro148Pro	synonymous	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes AF: 0.000199 AC: 30 AN: 150798 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000170

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: 0.000340

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000474 AC: 2 AN: 4218 AF XY: 0.000890

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: 0.000771

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00102 AC: 1212 AN: 1185550 Hom.: 2 Cov.: 28 AF XY: 0.000980 AC XY: 562 AN XY: 573500

African (AFR) AF: 0.000261 AC: 6 AN: 22998

American (AMR) AF: 0.00 AC: 0 AN: 9266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16012

East Asian (EAS) AF: 0.00 AC: 0 AN: 27188

South Asian (SAS) AF: 0.00 AC: 0 AN: 48048

European-Finnish (FIN) AF: 0.000106 AC: 3 AN: 28354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3300

European-Non Finnish (NFE) AF: 0.00121 AC: 1187 AN: 981752

Other (OTH) AF: 0.000329 AC: 16 AN: 48632

GnomAD4 genome AF: 0.000199 AC: 30 AN: 150798 Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 9 AN XY: 73618

African (AFR) AF: 0.000170 AC: 7 AN: 41104

American (AMR) AF: 0.00 AC: 0 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000340 AC: 23 AN: 67576

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000204

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Beckwith-Wiedemann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		-0.71
Mutation Taster		=100/0	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: rs878853625; hg19: chr11-2906276;