NM_000432.4:c.64G>T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000432.4(MYL2):c.64G>T(p.Glu22*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000432.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYL2 | NM_000432.4 | c.64G>T | p.Glu22* | stop_gained | Exon 2 of 7 | ENST00000228841.15 | NP_000423.2 | |
MYL2 | NM_001406745.1 | c.64G>T | p.Glu22* | stop_gained | Exon 2 of 6 | NP_001393674.1 | ||
MYL2 | NM_001406916.1 | c.7G>T | p.Glu3* | stop_gained | Exon 2 of 7 | NP_001393845.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYL2 | ENST00000228841.15 | c.64G>T | p.Glu22* | stop_gained | Exon 2 of 7 | 1 | NM_000432.4 | ENSP00000228841.8 | ||
MYL2 | ENST00000548438.1 | c.64G>T | p.Glu22* | stop_gained | Exon 2 of 6 | 3 | ENSP00000447154.1 | |||
MYL2 | ENST00000663220.1 | c.7G>T | p.Glu3* | stop_gained | Exon 2 of 7 | ENSP00000499568.1 | ||||
MYL2 | ENST00000546404.1 | c.64G>T | p.Glu22* | stop_gained | Exon 2 of 2 | 2 | ENSP00000499645.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135908
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461712Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727142
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
not provided Uncertain:1
p.Glu22Stop (GAA>TAA): c.64 G>T in exon 2 of the MYL2 gene (NM_000432.3). The Glu22Stop mutation in the MYL2 gene has been reported in one individual who was part of the Framingham and Jackson Heart Study cohort (Bick et al., 2012). This individual had left ventricular wall thickness that measured within in the normal range (Bick et al., 2012). Glu22 stop may cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, no other nonsense mutations in the MYL2 gene have been reported in association with HCM. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s). -
Cardiovascular phenotype Uncertain:1
The p.E22* variant (also known as c.64G>T), located in coding exon 2 of the MYL2 gene, results from a G to T substitution at nucleotide position 64. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. The predicted stop codon occurs in the 5’ end of theMYL2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant has been reported in one participant from the Jackson Heart Study cohort, whose echocardiogram values were not indicative of cardiac disease at the time of evaluation (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at