MYLK

Chr 3ADAR

myosin light chain kinase

Also known as: AAT7, KRP, MLCK, MLCK1, MLCK108, MLCK210, MMIHS, MMIHS1

NCBI Gene: 4638 ENSG00000065534 UniProt: Q15746

This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Aortic aneurysm, familial thoracic 7MIM #613780

Megacystis-microcolon-intestinal hypoperistalsis syndrome 1MIM #249210

569

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— MYLK

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Gene-Disease Validity (ClinGen)

familial thoracic aortic aneurysm and aortic dissection · ADStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 Pathogenic / Likely Pathogenic· 381 VUS of 569 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.53LOEUF

pLI 0.000

Z-score 5.23

OE 0.40 (0.30–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.13Z-score

OE missense 0.90 (0.85–0.95)

967 obs / 1071.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.40 (0.30–0.53)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.85–0.95)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02

0≤1.21.6

LoF obs/exp: 35 / 87.9Missense obs/exp: 967 / 1071.2Syn Z: -0.26