rs191294997

Variant names:

• chr11-2884935-A-C
• rs191294997
• NM_001122630.2:c.522T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-2884935-A-C
• chr11-2884935-A-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001122630.2(CDKN1C):​c.522T>G​(p.Ala174Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 765,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A174A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: CDKN1C NM_001122630.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 8 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.522T>G	p.Ala174Ala	synonymous_variant	Exon 2 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.522T>G	p.Ala174Ala	synonymous_variant	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000131 AC: 1 AN: 765552 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 362950

⚠️ 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: 14626

American (AMR) AF: 0.00 AC: 0 AN: 4428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8218

East Asian (EAS) AF: 0.00 AC: 0 AN: 12798

South Asian (SAS) AF: 0.00 AC: 0 AN: 14462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1916

European-Non Finnish (NFE) AF: 0.00000150 AC: 1 AN: 667260

Other (OTH) AF: 0.00 AC: 0 AN: 28748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 415

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.2
DANN	Benign	0.25
PhyloP100		-2.0

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: rs191294997; hg19: chr11-2906165;