rs749921840
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_053025.4(MYLK):c.4016G>T(p.Cys1339Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
MYLK
NM_053025.4 missense
NM_053025.4 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 4.31
Genes affected
MYLK (HGNC:7590): (myosin light chain kinase) 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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MYLK
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3636918).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.4016G>T | p.Cys1339Phe | missense_variant | 24/34 | ENST00000360304.8 | |
LOC124909421 | XR_007096038.1 | n.1066-1471C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.4016G>T | p.Cys1339Phe | missense_variant | 24/34 | 5 | NM_053025.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251096Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135754
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461540Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727078
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces cysteine with phenylalanine at codon 1339 of the MYLK protein (p.Cys1339Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs749921840, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2023 | The p.C1339F variant (also known as c.4016G>T), located in coding exon 21 of the MYLK gene, results from a G to T substitution at nucleotide position 4016. The cysteine at codon 1339 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;N;N;.;N;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;D;D;D
REVEL
Benign
Sift
Benign
T;.;T;D;D;D;T
Sift4G
Uncertain
D;D;D;D;D;D;.
Polyphen
D;D;D;D;D;D;.
Vest4
MutPred
Loss of catalytic residue at P1338 (P = 0.0094);.;Loss of catalytic residue at P1338 (P = 0.0094);Loss of catalytic residue at P1338 (P = 0.0094);.;Loss of catalytic residue at P1338 (P = 0.0094);.;
MVP
MPC
0.27
ClinPred
D
GERP RS
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gMVP
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