2-130598681-G-GCCCCCAGCCCTC
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_032545.4(CFC1):c.207_208insGAGGGCTGGGGG(p.Glu66_Gly69dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 22)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CFC1
NM_032545.4 inframe_insertion
NM_032545.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.606
Genes affected
CFC1 (HGNC:18292): (cryptic, EGF-CFC family member 1) This gene encodes a member of the epidermal growth factor (EGF)- Cripto, Frl-1, and Cryptic (CFC) family, which are involved in signalling during embryonic development. Proteins in this family share a variant EGF-like motif, a conserved cysteine-rich domain, and a C-terminal hydrophobic region. The protein encoded by this gene is necessary for patterning the left-right embryonic axis. Mutations in this gene are associated with defects in organ development, including autosomal visceral heterotaxy and congenital heart disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_032545.4.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFC1 | NM_032545.4 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/6 | ENST00000259216.6 | NP_115934.1 | |
CFC1 | NM_001270420.2 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/5 | NP_001257349.1 | ||
CFC1 | NM_001270421.2 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/4 | NP_001257350.1 | ||
CFC1 | XM_011511486.4 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/4 | XP_011509788.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFC1 | ENST00000259216.6 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/6 | 1 | NM_032545.4 | ENSP00000259216 | P1 | |
CFC1 | ENST00000615342.4 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/5 | 5 | ENSP00000480526 | |||
CFC1 | ENST00000621673.4 | c.207_208insGAGGGCTGGGGG | p.Glu66_Gly69dup | inframe_insertion | 3/4 | 2 | ENSP00000480843 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 22
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000479 AC: 7AN: 1461626Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727126
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 22 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2023 | Variant summary: CFC1 c.196_207dup12 (p.Glu66_Gly69dup) results in an in-frame duplication that is predicted to duplicate 4 amino acids into the encoded protein. The variant was absent in 247428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.196_207dup12 in individuals affected with Heterotaxy, Visceral, 2, Autosomal and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at