12-110913124-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000432.4(MYL2):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000035 ( 0 hom. )
Consequence
MYL2
NM_000432.4 missense
NM_000432.4 missense
Scores
12
6
2
Clinical Significance
Conservation
PhyloP100: 9.55
Genes affected
MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000432.4
BS2
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYL2 | NM_000432.4 | c.374C>T | p.Thr125Met | missense_variant | 6/7 | ENST00000228841.15 | NP_000423.2 | |
MYL2 | NM_001406745.1 | c.332C>T | p.Thr111Met | missense_variant | 5/6 | NP_001393674.1 | ||
MYL2 | NM_001406916.1 | c.317C>T | p.Thr106Met | missense_variant | 6/7 | NP_001393845.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYL2 | ENST00000228841.15 | c.374C>T | p.Thr125Met | missense_variant | 6/7 | 1 | NM_000432.4 | ENSP00000228841.8 | ||
MYL2 | ENST00000548438.1 | c.332C>T | p.Thr111Met | missense_variant | 5/6 | 3 | ENSP00000447154.1 | |||
MYL2 | ENST00000663220.1 | c.317C>T | p.Thr106Met | missense_variant | 6/7 | ENSP00000499568.1 | ||||
MYL2 | ENST00000549029.1 | n.*9C>T | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000107 AC: 27AN: 251492Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135922
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GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22AN XY: 727248
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GnomAD4 genome AF: 0.0000919 AC: 14AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID 43473; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33297573) - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 03, 2021 | This missense variant replaces threonine with methionine at codon 125 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33297573). This variant has also been identified in 30/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 06, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 27, 2011 | Variant classified as Uncertain Significance - Favor Benign. The Thr125Met varia nt in MYL2 has been identified in 1/8600 European American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). and in 1 indiv idual with HCM (this individual's relative, who carries a pathogenic MYBPC3 vari ant). Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an i mpact to the protein. Additional studies are needed to fully assess its clinical significance. - |
Hypertrophic cardiomyopathy 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the MYL2 protein (p.Thr125Met). This variant is present in population databases (rs375667565, gnomAD 0.1%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33297573, 34598319, 35626289). ClinVar contains an entry for this variant (Variation ID: 43473). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 14, 2024 | This missense variant replaces threonine with methionine at codon 125 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33297573). This variant has also been identified in 30/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2018 | The c.374C>T (p.T125M) alteration is located in exon 6 (coding exon 6) of the MYL2 gene. This alteration results from a C to T substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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