chr12-110919113-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000432.4(MYL2):c.84A>T(p.Glu28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E28G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000432.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYL2 | NM_000432.4 | c.84A>T | p.Glu28Asp | missense_variant | 2/7 | ENST00000228841.15 | |
MYL2 | NM_001406745.1 | c.84A>T | p.Glu28Asp | missense_variant | 2/6 | ||
MYL2 | NM_001406916.1 | c.27A>T | p.Glu9Asp | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYL2 | ENST00000228841.15 | c.84A>T | p.Glu28Asp | missense_variant | 2/7 | 1 | NM_000432.4 | P1 | |
MYL2 | ENST00000548438.1 | c.84A>T | p.Glu28Asp | missense_variant | 2/6 | 3 | |||
MYL2 | ENST00000663220.1 | c.27A>T | p.Glu9Asp | missense_variant | 2/7 | ||||
MYL2 | ENST00000546404.1 | c.84A>T | p.Glu28Asp | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 31, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Glu28Asp va riant in MYL2 has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). While this low frequency is consist ent with a disease-causing role, it is insufficient to establish this with confi dence. Glutamic acid (Glu) at position 28 is highly conserved in evolution and t he change to asparagine (Asp) was predicted to be pathogenic using a computation al tool, which was validated by our laboratory using a set of cardiomyopathy var iants with well-established clinical significance. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). This variant is m ore likely pathogenic but additional studies are needed to fully assess its clin ical significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at