rs146990616
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_053025.4(MYLK):c.5368+13_5368+21del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,603,516 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0054 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0066 ( 40 hom. )
Consequence
MYLK
NM_053025.4 intron
NM_053025.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.23
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 -16 ACMG points.
BP6
?
Variant 3-123620185-GGCTGGAGAA-G is Benign according to our data. Variant chr3-123620185-GGCTGGAGAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 420653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123620185-GGCTGGAGAA-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00537 (817/152046) while in subpopulation NFE AF= 0.00865 (588/67990). AF 95% confidence interval is 0.00807. There are 2 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.5368+13_5368+21del | intron_variant | ENST00000360304.8 | |||
MYLK-AS1 | NR_038266.2 | n.290-9308_290-9300del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.5368+13_5368+21del | intron_variant | 5 | NM_053025.4 | P4 | |||
MYLK-AS1 | ENST00000485162.5 | n.261-9308_261-9300del | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00538 AC: 817AN: 151960Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00511 AC: 1284AN: 251332Hom.: 8 AF XY: 0.00540 AC XY: 733AN XY: 135846
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GnomAD4 exome AF: 0.00665 AC: 9649AN: 1451470Hom.: 40 AF XY: 0.00658 AC XY: 4759AN XY: 722778
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GnomAD4 genome ? AF: 0.00537 AC: 817AN: 152046Hom.: 2 Cov.: 32 AF XY: 0.00509 AC XY: 378AN XY: 74316
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2021 | Variant summary: MYLK c.5368+13_5368+21delTTCTCCAGC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0051 in 251332 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 102-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Thoracic Aortic Aneurysms And Dissections phenotype (5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.5368+13_5368+21delTTCTCCAGC in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Aortic aneurysm, familial thoracic 7 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 27, 2023 | - - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at