15-66703712-CCGGCGGG-C
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PVS1PP5BS2
The NM_005585.5(SMAD6):c.465_471delCGGGCGG(p.Gly156ValfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,346,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G155G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005585.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.465_471delCGGGCGG | p.Gly156ValfsTer23 | frameshift_variant | Exon 1 of 4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | NR_027654.2 | n.1488_1494delCGGGCGG | non_coding_transcript_exon_variant | Exon 1 of 5 | ||||
SMAD6 | XR_931827.3 | n.1488_1494delCGGGCGG | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.465_471delCGGGCGG | p.Gly156ValfsTer23 | frameshift_variant | Exon 1 of 4 | 1 | NM_005585.5 | ENSP00000288840.5 | ||
SMAD6 | ENST00000557916.5 | n.465_471delCGGGCGG | non_coding_transcript_exon_variant | Exon 1 of 5 | 1 | ENSP00000452955.1 | ||||
SMAD6 | ENST00000612349.1 | n.647_653delCGGGCGG | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes AF: 0.0000133 AC: 2AN: 150106Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.0000142 AC: 17AN: 1196836Hom.: 0 AF XY: 0.00000683 AC XY: 4AN XY: 585938 show subpopulations
GnomAD4 genome AF: 0.0000133 AC: 2AN: 150106Hom.: 0 Cov.: 32 AF XY: 0.0000273 AC XY: 2AN XY: 73216 show subpopulations
ClinVar
Submissions by phenotype
Craniosynostosis 7 Pathogenic:1
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Craniosynostosis syndrome Pathogenic:1
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Radioulnar synostosis Uncertain:1
PVS1, PM2, PP4, BS4 -
Aortic valve disease 2 Uncertain:1
This sequence change creates a premature translational stop signal (p.Gly156Valfs*23) in the SMAD6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SMAD6 cause disease. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sagittal craniosynostosis, bicuspid aortic valve-associated thoracic aortic aneurysm and/or radioulnar synostosis (PMID: 28659821, 28808027, 31138930). ClinVar contains an entry for this variant (Variation ID: 638816). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Reported in a patient with craniosynostosis who also harbored an additional potentially disease-causing variant in the TCF12 gene (Timberlake et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease.; This variant is associated with the following publications: (PMID: 28659821, 30038786, 31138930, 28808027) -
Radioulnar synostosis, nonsyndromic, susceptibility to Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at