rs142835596

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_053025.4(MYLK):​c.2101G>A​(p.Ala701Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,186 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 12 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 6 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

2
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0310
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=0.012049317).
BP6
Variant 3-123708737-C-T is Benign according to our data. Variant chr3-123708737-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123708737-C-T is described in Lovd as [Benign]. Variant chr3-123708737-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00587 (895/152352) while in subpopulation AFR AF= 0.0201 (837/41578). AF 95% confidence interval is 0.019. There are 12 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYLKNM_053025.4 linkuse as main transcriptc.2101G>A p.Ala701Thr missense_variant 15/34 ENST00000360304.8 NP_444253.3
LOC105369194XR_924417.4 linkuse as main transcriptn.252-3620C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYLKENST00000360304.8 linkuse as main transcriptc.2101G>A p.Ala701Thr missense_variant 15/345 NM_053025.4 ENSP00000353452 P4Q15746-1
ENST00000685586.1 linkuse as main transcriptn.612-3620C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00583
AC:
887
AN:
152234
Hom.:
12
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0200
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00281
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00525
GnomAD3 exomes
AF:
0.00146
AC:
366
AN:
251314
Hom.:
2
AF XY:
0.00109
AC XY:
148
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.0202
Gnomad AMR exome
AF:
0.000838
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000534
AC:
780
AN:
1461834
Hom.:
6
Cov.:
31
AF XY:
0.000483
AC XY:
351
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.0182
Gnomad4 AMR exome
AF:
0.00123
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.00111
GnomAD4 genome
AF:
0.00587
AC:
895
AN:
152352
Hom.:
12
Cov.:
32
AF XY:
0.00565
AC XY:
421
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0201
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.00106
Hom.:
0
Bravo
AF:
0.00683
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.0197
AC:
87
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00181
AC:
220
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJan 16, 2020- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 30, 2016- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 28, 2022- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:3
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 16, 2022- -
Aortic aneurysm, familial thoracic 7 Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 22, 2015This alteration is classified as 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. -
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 23, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
.;.;.;T;.;T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.056
N
LIST_S2
Benign
0.78
.;T;T;T;.;.
MetaRNN
Benign
0.012
T;T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.3
M;.;M;M;.;M
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.3
N;.;N;N;N;N
REVEL
Benign
0.13
Sift
Benign
0.30
T;.;T;T;T;T
Sift4G
Benign
0.34
T;T;T;T;T;T
Polyphen
0.28
B;B;B;B;B;B
Vest4
0.31
MVP
0.63
MPC
0.21
ClinPred
0.0024
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.023
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142835596; hg19: chr3-123427584; COSMIC: COSV100659751; COSMIC: COSV100659751; API