rs3746597
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.His183His) 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
Consequence
NM_033118.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYLK2 | ENST00000375985.5 | c.549C>T | p.His183His | synonymous_variant | Exon 4 of 13 | 1 | NM_033118.4 | ENSP00000365152.4 | ||
MYLK2 | ENST00000375994.6 | c.549C>T | p.His183His | synonymous_variant | Exon 3 of 12 | 1 | ENSP00000365162.2 |
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152258Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00131 AC: 329AN: 251068Hom.: 4 AF XY: 0.00123 AC XY: 167AN XY: 135810
GnomAD4 exome AF: 0.000573 AC: 838AN: 1461680Hom.: 6 Cov.: 32 AF XY: 0.000534 AC XY: 388AN XY: 727138
GnomAD4 genome AF: 0.000538 AC: 82AN: 152376Hom.: 1 Cov.: 33 AF XY: 0.000684 AC XY: 51AN XY: 74512
ClinVar
Submissions by phenotype
not specified Benign:4
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. -
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. -
2.5% (18/734) Asian alleles from JBIC-allele - East Asian population in dbSNP -
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. -
MYLK2-related disorder Benign:1
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
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not provided Benign:1
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Hypertrophic cardiomyopathy 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at