rs727504591
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_033118.4(MYLK2):c.557C>T(p.Thr186Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T186T) has been classified as Likely benign.
Frequency
Consequence
NM_033118.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK2 | NM_033118.4 | c.557C>T | p.Thr186Met | missense_variant | 4/13 | ENST00000375985.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK2 | ENST00000375985.5 | c.557C>T | p.Thr186Met | missense_variant | 4/13 | 1 | NM_033118.4 | P1 | |
MYLK2 | ENST00000375994.6 | c.557C>T | p.Thr186Met | missense_variant | 3/12 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000996 AC: 25AN: 251046Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135814
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461680Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 727136
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Thr186Met varia nt in MYLK2 has not been reported in individuals with cardiomyopathy or in large population studies. Threonine (Thr) at position 186 is not well conserved in ev olution and several mammals (bushbaby, megabat and sloth) have a methionine (Met ) at this position, suggesting that this change may be tolerated. Additional com putational analyses (AlignGVGD, PolyPhen2, and SIFT) do not suggest a high likel ihood of impact to the protein. In summary, the lack of conservation and presenc e of this variant in other species suggests that this variant may be benign, but additional studies are needed to fully assess the clinical significance of this variant. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2020 | Variant summary: MYLK2 c.557C>T (p.Thr186Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251046 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.557C>T in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2024 | The p.T186M variant (also known as c.557C>T), located in coding exon 3 of the MYLK2 gene, results from a C to T substitution at nucleotide position 557. The threonine at codon 186 is replaced by methionine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 06, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 08, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYLK2 protein function. ClinVar contains an entry for this variant (Variation ID: 178986). This variant has not been reported in the literature in individuals affected with MYLK2-related conditions. This variant is present in population databases (rs727504591, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 186 of the MYLK2 protein (p.Thr186Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at