rs398124034
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The ENST00000357033.9(DMD):c.676_678del(p.Lys226del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K226K) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
DMD
ENST00000357033.9 inframe_deletion
ENST00000357033.9 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.52
Genes affected
DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in ENST00000357033.9. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant X-32699264-ACTT-A is Pathogenic according to our data. Variant chrX-32699264-ACTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 94746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32699264-ACTT-A is described in Lovd as [Pathogenic]. Variant chrX-32699264-ACTT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.676_678del | p.Lys226del | inframe_deletion | 8/79 | ENST00000357033.9 | NP_003997.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.676_678del | p.Lys226del | inframe_deletion | 8/79 | 1 | NM_004006.3 | ENSP00000354923 | P4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2023 | Published functional studies demonstrate decreased dystrophin on Western blot (Aartsma-Rus et al., 2006); In-frame deletion of 1 amino acids in a non-repeat region predicted to critically alter the protein length. Deleted amino acid residue is predicted to be within the CH domain 2 in the actin binding domain; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21515508, 19937601, 27582364, 20485447, 33101180, 33644936, 29973226, 19760747) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 21, 2016 | - - |
Duchenne muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 16, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 94746). This variant has been observed in individuals with Becker/Duchenne muscular dystrophy (PMID: 19760747, 20485447, 21515508, 27582364). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.676_678del, results in the deletion of 1 amino acid(s) of the DMD protein (p.Lys226del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at