rs3746597
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_033118.4(MYLK2):c.549C>T(p.His183=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,614,056 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00054 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00057 ( 6 hom. )
Consequence
MYLK2
NM_033118.4 synonymous
NM_033118.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.35
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 20-31821514-C-T is Benign according to our data. Variant chr20-31821514-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.35 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000573 (838/1461680) while in subpopulation EAS AF= 0.0193 (765/39700). AF 95% confidence interval is 0.0181. There are 6 homozygotes in gnomad4_exome. There are 388 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 82 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYLK2 | NM_033118.4 | c.549C>T | p.His183= | synonymous_variant | 4/13 | ENST00000375985.5 | NP_149109.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYLK2 | ENST00000375985.5 | c.549C>T | p.His183= | synonymous_variant | 4/13 | 1 | NM_033118.4 | ENSP00000365152 | P1 | |
MYLK2 | ENST00000375994.6 | c.549C>T | p.His183= | synonymous_variant | 3/12 | 1 | ENSP00000365162 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152258Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00131 AC: 329AN: 251068Hom.: 4 AF XY: 0.00123 AC XY: 167AN XY: 135810
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GnomAD4 exome AF: 0.000573 AC: 838AN: 1461680Hom.: 6 Cov.: 32 AF XY: 0.000534 AC XY: 388AN XY: 727138
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GnomAD4 genome AF: 0.000538 AC: 82AN: 152376Hom.: 1 Cov.: 33 AF XY: 0.000684 AC XY: 51AN XY: 74512
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 17, 2023 | Variant summary: MYLK2 c.549C>T results in a synonymous change. The variant allele was found at a frequency of 0.0013 in 251068 control chromosomes, predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 700 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 a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.549C>T in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 01, 2012 | 2.5% (18/734) Asian alleles from JBIC-allele - East Asian population in dbSNP - |
MYLK2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 19, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 19, 2016 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Hypertrophic cardiomyopathy 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at