NM_001122630.2:c.537G>A

Variant names:

• chr11-2884920-C-T
• rs550978405
• NM_001122630.2:c.537G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001122630.2(CDKN1C):​c.537G>A​(p.Pro179Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 141,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P179P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.76
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-2884920-C-T is Benign according to our data. Variant chr11-2884920-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1387607.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.76 with no splicing effect.

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.537G>A	p.Pro179Pro	synonymous	Exon 2 of 4	NP_001116102.1
	CDKN1C	NM_000076.2		c.570G>A	p.Pro190Pro	synonymous	Exon 1 of 3	NP_000067.1
	CDKN1C	NM_001362474.2		c.570G>A	p.Pro190Pro	synonymous	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.537G>A	p.Pro179Pro	synonymous	Exon 2 of 4	ENSP00000411257.2
	CDKN1C	ENST00000414822.8	TSL:1	c.570G>A	p.Pro190Pro	synonymous	Exon 1 of 3	ENSP00000413720.3
	CDKN1C	ENST00000430149.3	TSL:1	c.570G>A	p.Pro190Pro	synonymous	Exon 1 of 3	ENSP00000411552.2

Frequencies

GnomAD3 genomes AF: 0.00000709 AC: 1 AN: 141130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000267

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 707440 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 334320

African (AFR) AF: 0.00 AC: 0 AN: 12030

American (AMR) AF: 0.00 AC: 0 AN: 3336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6620

East Asian (EAS) AF: 0.00 AC: 0 AN: 8240

South Asian (SAS) AF: 0.00 AC: 0 AN: 13980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 627180

Other (OTH) AF: 0.00 AC: 0 AN: 25480

GnomAD4 genome AF: 0.00000708 AC: 1 AN: 141222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 68804

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

African (AFR) AF: 0.0000266 AC: 1 AN: 37528

American (AMR) AF: 0.00 AC: 0 AN: 14524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 4884

South Asian (SAS) AF: 0.00 AC: 0 AN: 4616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64714

Other (OTH) AF: 0.00 AC: 0 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000905 Hom.: 0

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.9
DANN	Uncertain	0.98
PhyloP100		-3.8

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: rs550978405; hg19: chr11-2906150;