20-31833747-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_033118.4(MYLK2):c.1741C>T(p.Arg581Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R581H) has been classified as Uncertain significance.
Frequency
Consequence
NM_033118.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK2 | NM_033118.4 | c.1741C>T | p.Arg581Cys | missense_variant | 13/13 | ENST00000375985.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK2 | ENST00000375985.5 | c.1741C>T | p.Arg581Cys | missense_variant | 13/13 | 1 | NM_033118.4 | P1 | |
MYLK2 | ENST00000375994.6 | c.1741C>T | p.Arg581Cys | missense_variant | 12/12 | 1 | P1 | ||
MYLK2 | ENST00000468730.1 | n.679C>T | non_coding_transcript_exon_variant | 6/6 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250450Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135410
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461646Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727146
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2024 | Variant summary: MYLK2 c.1741C>T (p.Arg581Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250450 control chromosomes, predominantly at a frequency of 0.00013 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1741C>T has been reported in the literature in an individual affected with Hypertrophic Cardiomyopathy without strong evidence for causality (example: Robyns_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31513939). ClinVar contains an entry for this variant (Variation ID: 228940). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 03, 2015 | The p.Arg581Cys variant in MYLK2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/66596 European chromosomes an d 2/16512 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org). Computational prediction tools and conservation an alysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical s ignificance of the p.Arg581Cys variant is uncertain. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at