rs150936840
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong
The NM_053025.4(MYLK):c.2149G>T(p.Asp717Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,614,050 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
MYLK
NM_053025.4 missense
NM_053025.4 missense
Scores
4
9
5
Clinical Significance
Conservation
PhyloP100: 6.93
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 Benign. Variant got -11 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYLK. . Gene score misZ 1.1317 (greater than the threshold 3.09). Trascript score misZ 3.1503 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, megacystis-microcolon-intestinal hypoperistalsis syndrome, aortic aneurysm, familial thoracic 7.
BP4
Computational evidence support a benign effect (MetaRNN=0.010325998).
BP6
Variant 3-123707995-C-A is Benign according to our data. Variant chr3-123707995-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 216969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.2149G>T | p.Asp717Tyr | missense_variant | 16/34 | ENST00000360304.8 | NP_444253.3 | |
LOC105369194 | XR_924417.4 | n.251+3986C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.2149G>T | p.Asp717Tyr | missense_variant | 16/34 | 5 | NM_053025.4 | ENSP00000353452 | P4 | |
ENST00000685586.1 | n.611+3986C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000355 AC: 89AN: 250672Hom.: 0 AF XY: 0.000354 AC XY: 48AN XY: 135572
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GnomAD4 exome AF: 0.000105 AC: 154AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.000116 AC XY: 84AN XY: 727180
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GnomAD4 genome AF: 0.000190 AC: 29AN: 152268Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74454
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 7 Pathogenic:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
Likely pathogenic, flagged submission | clinical testing | UCLA Clinical Genomics Center, UCLA | Jan 29, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2018 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;.;.
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;L;.;L
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;N;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;D;D;D
Vest4
MVP
MPC
0.20
ClinPred
T
GERP RS
Varity_R
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