GeneBe

MYLK2

protein-coding

myosin light chain kinase 2, the group of Myosin light chain kinase family

Gene summary

This gene encodes a myosin light chain kinase, a calcium/calmodulin dependent enzyme, that is exclusively expressed in adult skeletal muscle. [provided by RefSeq, Jul 2008]

MANE transcript

NM_033118.4

Inheritance

AD, Digenic

ClinVar variants

U:404B:233

Top phenotype

Cardiomyopathy, hypertrophic 1, digenic

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr20:31,819,308-31,834,689

External References & Databases

Ensembl (ENSG00000101306)NCBI Gene (85366)OMIM (606566)HGNC:16243GenCCUniProt (Q9H1R3)AlphaFoldClinVar (MYLK2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~15.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypertrophic cardiomyopathy 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008647

Submitter: Labcorp Genetics (formerly Invitae)

hypertrophic cardiomyopathy 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008647

Submitter: PanelApp Australia

hypertrophic cardiomyopathy 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008647

Submitter: Ambry Genetics

hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

*MYLK2* was first reported in relation to hypertrophic cardiomyopathy (HCM) in humans as early as 2001(Davis et al., 2001 PMID: 11733062). To date, at least 5 unique variants (4 missense, 1 synonymous) have been reported in 4 probands with hypertrophic cardiomyopathy (Davis et al., 2001, PMID: 11733062; Wang et al., 2018, PMID: 29978770; Gonzalez-Garay et al., 2013, PMID:24082139; Burstein et al., 2021, PMID:32746448). However, these probands also carry additional variants in genes implicated in hypertrophic cardiomyopathy, including MYH7 and MYBPC3. No segregation data is available. The mechanism for disease is unknown, but predicted to be gain of function (GOF) from functional assays performed by Davis et al., 2001. This gene-disease relationship is supported by expression studies showing restricted expression of MYLK2 in skeletal muscle and heart and biochemical functional studies. The original curation was performed by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel (GCEP) and published on January 18, 2017. In summary, there is no scored genetic evidence, and no new convincing evidence has emerged that contradicts the gene-disease relationship. More evidence is needed to either support or entirely refute the role MYLK2 plays in this disease. This classification was re-evaluated and approved by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel on February 8, 2023. As a result of this re-evaluation, the classification was changed from limited to disputed.

familial hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Clinical Genomic Database (CGD)

Cardiomyopathy, hypertrophic 1, digenicAD/Digenic

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Surveillance for cardiomyopathy (eg, with echocardiography/electrocardiography) and early medical treatment may reduce morbidity

Comments: Digenic inheritance (with MYH7) has been described

Refs: 11733062Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYLK2 variants in ClinVar

14 Conditions Cataloged
Hypertrophic cardiomyopathy 1Total: 531
not specifiedTotal: 401
not providedTotal: 146
CardiomyopathyTotal: 37
MYLK2-related disorderTotal: 30
Hypertrophic cardiomyopathyTotal: 8
See casesTotal: 2
Ventricular tachycardiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033118.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
200
clinvar
1
clinvar
 204
missense
377
clinvar
31
clinvar
1
clinvar
 409
nonsense
3
clinvar
 3
start loss
1
clinvar
 1
frameshift
15
clinvar
 15
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total004042312637
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_033118.4RefSeqNP_149109.112MANE Select
ENST00000375985.5EnsemblENSP00000365152.412MANE Select
ENST00000375994.6EnsemblENSP00000365162.212Standard
ENST00000375994.7EnsemblENSP00000365162.212Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Platelet activation - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • Oxytocin signaling pathway - Homo sapiens (human)
  • Gastric acid secretion - Homo sapiens (human)
  • Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

  • striated muscle contraction
  • neuromuscular synaptic transmission
  • positive regulation of gene expression
  • skeletal muscle satellite cell differentiation
  • peptidyl-threonine phosphorylation

Molecular Function

  • calmodulin-dependent protein kinase activity
  • myosin light chain kinase activity
  • protein binding
  • calmodulin binding
  • ATP binding

Cellular Component

  • nucleus
  • cytoplasm
  • sarcomere

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000375994
Coding exons
12
Length
15382
Individuals with no LoFs
125724
Homozygous LoFs
1
Heterozygous LoFs
23
Defined
125748
p
0.0000954
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2253253370.9650.00001953914
Missense (PolyPhen)101117.160.862061428
Synonymous-0.3421441391.040.000009351166
Loss of Function3.50624.80.2420.00000117319

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000130.00012rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish00.0absent
European (Non-Finnish)0.0000810.000079rare
South Asian0.000130.000098rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Implicated in the level of global muscle contraction and cardiac function. Phosphorylates a specific serine in the N- terminus of a myosin light chain. {ECO:0000269|PubMed:11733062}.;

Recessive Scores

pRec
0.150

Intolerance Scores

LoFtool
0.498
RVIS EVS
-0.24
RVIS percentile EVS
36.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.947

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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