NM_000432.4:c.4G>T
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1PP2BP4_ModerateBP6
The NM_000432.4(MYL2):c.4G>T(p.Ala2Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 20/25 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000432.4 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 10Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathyInheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
- congenital fiber-type disproportion myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYL2 | NM_000432.4 | c.4G>T | p.Ala2Ser | missense_variant, splice_region_variant | Exon 2 of 7 | ENST00000228841.15 | NP_000423.2 | |
MYL2 | NM_001406745.1 | c.4G>T | p.Ala2Ser | missense_variant, splice_region_variant | Exon 2 of 6 | NP_001393674.1 | ||
MYL2 | NM_001406916.1 | c.-54G>T | splice_region_variant | Exon 2 of 7 | NP_001393845.1 | |||
MYL2 | NM_001406916.1 | c.-54G>T | 5_prime_UTR_variant | Exon 2 of 7 | NP_001393845.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151954Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250904 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460640Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726584 show subpopulations
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151954Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74198 show subpopulations
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 10 Uncertain:1
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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYL2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 2 of the MYL2 protein (p.Ala2Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. -
Cardiomyopathy Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at