rs387907225

Variant names:

• chr11-2884670-C-A
• rs387907225
• NM_001122630.2:c.787G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2884670-C-A
• chr11-2884670-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001122630.2(CDKN1C):​c.787G>T​(p.Asp263Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,232,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D263N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.556
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• IMAGe syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P, Ambry Genetics
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_001122630.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2884670-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 35531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	NM_001122630.2	MANE Select	c.787G>T	p.Asp263Tyr	missense splice_region	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.820G>T	p.Asp274Tyr	missense splice_region	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.820G>T	p.Asp274Tyr	missense splice_region	Exon 1 of 3	NP_001349403.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.787G>T	p.Asp263Tyr	missense splice_region	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.820G>T	p.Asp274Tyr	missense splice_region	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.820G>T	p.Asp274Tyr	missense splice_region	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1232276 Hom.: 0 Cov.: 29 AF XY: 0.00000165 AC XY: 1 AN XY: 607322

⚠️ 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: 25082

American (AMR) AF: 0.00 AC: 0 AN: 21442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17676

East Asian (EAS) AF: 0.00 AC: 0 AN: 28620

South Asian (SAS) AF: 0.00 AC: 0 AN: 59616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3806

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 997250

Other (OTH) AF: 0.00 AC: 0 AN: 48762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.099
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.56
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.34		Gain of catalytic residue at D274 (P = 0.0464)
MVP		0.92
MPC		1.5
ClinPred		0.98	D
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.58
gMVP		0.32
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387907225; hg19: chr11-2905900;