1-25809104-G-GCCT
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4_SupportingPP3PP5_Very_Strong
The NM_020451.3(SELENON):c.827_829dupCCT(p.Ala276_Cys277insSer) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_020451.3 disruptive_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.827_829dupCCT | p.Ala276_Cys277insSer | disruptive_inframe_insertion | Exon 6 of 13 | ENST00000361547.7 | NP_065184.2 | |
SELENON | NM_206926.2 | c.725_727dupCCT | p.Ala242_Cys243insSer | disruptive_inframe_insertion | Exon 5 of 12 | NP_996809.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.827_829dupCCT | p.Ala276_Cys277insSer | disruptive_inframe_insertion | Exon 6 of 13 | 1 | NM_020451.3 | ENSP00000355141.2 | ||
SELENON | ENST00000374315.1 | c.725_727dupCCT | p.Ala242_Cys243insSer | disruptive_inframe_insertion | Exon 5 of 12 | 5 | ENSP00000363434.1 | |||
SELENON | ENST00000354177.9 | c.656_658dupCCT | p.Ala219_Cys220insSer | disruptive_inframe_insertion | Exon 5 of 12 | 5 | ENSP00000346109.5 | |||
SELENON | ENST00000494537.2 | n.725_727dupCCT | non_coding_transcript_exon_variant | Exon 5 of 13 | 3 | ENSP00000508308.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152258Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249302Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135384
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461430Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727018
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
Congenital myopathy with fiber type disproportion Pathogenic:1
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Congenital myopathy 4A, autosomal dominant Pathogenic:1
The inframe insertion variant c.827_829dup (p.Ala276_Cys277insSer) has been submitted to ClinVar as Likely Pathogenic. It has been reported previously using alternate nomenclature (c.829_829insTCC) in the homozygous state in an individual with significant neck extensor and flexor weakness, mild axial and limb girdle weakness, and developmental delay (Ardissone et al., 2016). This p.Ala276_Cys277insSer variant has allele frequency of 0.0008% in the gnomAD and novel (not in any individuals) in 1000 genome database . The insertion of amino acid Ser between amino acids Ala at position 276 and Cys at position 277 changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant , the molecular diagnosis is not confirmed. -
Eichsfeld type congenital muscular dystrophy Pathogenic:1
The p.Ala276_Cys277insSer variant in SELENON has been reported in 2 individuals with SELENON-RM (PMID: 30932294, 26780752) and has been identified in 0.007% (2/30600) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1329981323). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 212149) and has been interpreted as likely pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the p.Ala276_Cys277insSer variant is pathogenic (PMID: 30932294, 26780752). In vitro functional studies provide some evidence that the p.Ala276_Cys277insSer variant may impact protein function (PMID: 30932294). However, these types of assays may not accurately represent biological function. This variant is an insertion of 1 amino acid at position 276 and is not predicted to alter the protein reading-frame. This insertion is expected to impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM2_supporting, PM4_supporting (Richards 2015). -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 26780752, 30932294, 31069529) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at