rs765135888
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_017534.6(MYH2):āc.4376T>Cā(p.Leu1459Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_017534.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.4376T>C | p.Leu1459Pro | missense_variant | 32/40 | ENST00000245503.10 | |
MYHAS | NR_125367.1 | n.168-41925A>G | intron_variant, non_coding_transcript_variant | ||||
MYH2 | NM_001100112.2 | c.4376T>C | p.Leu1459Pro | missense_variant | 32/40 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH2 | ENST00000245503.10 | c.4376T>C | p.Leu1459Pro | missense_variant | 32/40 | 1 | NM_017534.6 | P1 | |
ENST00000399342.6 | n.207-7712A>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251230Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Myopathy, proximal, and ophthalmoplegia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2017 | 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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 MYH2-related disease. This variant is present in population databases (rs765135888, ExAC 0.001%). This sequence change replaces leucine with proline at codon 1459 of the MYH2 protein (p.Leu1459Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at