rs990598927
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000288840.10(SMAD6):c.194C>G(p.Pro65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000099 in 1,272,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65L) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000288840.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.194C>G | p.Pro65Arg | missense_variant | 1/4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | NR_027654.2 | n.1217C>G | non_coding_transcript_exon_variant | 1/5 | ||||
SMAD6 | XR_931827.3 | n.1217C>G | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.194C>G | p.Pro65Arg | missense_variant | 1/4 | 1 | NM_005585.5 | ENSP00000288840 | P1 | |
SMAD6 | ENST00000557916.5 | c.194C>G | p.Pro65Arg | missense_variant, NMD_transcript_variant | 1/5 | 1 | ENSP00000452955 | |||
SMAD6 | ENST00000612349.1 | n.376C>G | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.000119 AC: 18AN: 151660Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000963 AC: 108AN: 1120954Hom.: 0 Cov.: 32 AF XY: 0.0000860 AC XY: 46AN XY: 534936
GnomAD4 genome AF: 0.000119 AC: 18AN: 151768Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4AN XY: 74172
ClinVar
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 | Aug 24, 2023 | - - |
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 65 of the SMAD6 protein (p.Pro65Arg). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 405518). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at