rs3732485

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_053025.4(MYLK):c.2533C>T(p.Arg845Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,611,056 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R845H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 62 hom., cov: 30)

Exomes 𝑓: 0.012 ( 586 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.0490

Publications

13 publications found

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]

MYLK links:

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

MYLK-AS1 links:

LOC105369194 (HGNC:):

LOC105369194 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014624298).

BP6

Variant 3-123700935-G-A is Benign according to our data. Variant chr3-123700935-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.2533C>T	p.Arg845Cys	missense_variant	Exon 18 of 34	ENST00000360304.8	NP_444253.3	Q15746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 link	c.2533C>T	p.Arg845Cys	missense_variant	Exon 18 of 34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2477

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.0484

Gnomad SAS

AF:

0.0856

Gnomad FIN

AF:

0.0660

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0270

AC:

6650

AN:

246212

AF XY:

0.0293

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.0297

Gnomad ASJ exome

AF:

0.00331

Gnomad EAS exome

AF:

0.0505

Gnomad FIN exome

AF:

0.0582

Gnomad NFE exome

AF:

0.00375

Gnomad OTH exome

AF:

0.0190

GnomAD4 exome

AF:

0.0117

AC:

17118

AN:

1458928

Hom.:

586

Cov.:

AF XY:

0.0140

AC XY:

10192

AN XY:

725962

show subpopulations

African (AFR)

AF:

0.0157

AC:

525

AN:

33480

American (AMR)

AF:

0.0269

AC:

1204

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00333

AC:

AN:

26136

East Asian (EAS)

AF:

0.0398

AC:

1579

AN:

39700

South Asian (SAS)

AF:

0.0871

AC:

7511

AN:

86258

European-Finnish (FIN)

AF:

0.0535

AC:

2704

AN:

50502

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00225

AC:

2506

AN:

1111990

Other (OTH)

AF:

0.0154

AC:

931

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1299

2598

3896

5195

6494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0163

AC:

2484

AN:

152128

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1490

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0164

AC:

680

AN:

41512

American (AMR)

AF:

0.0116

AC:

178

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.0481

AC:

247

AN:

5132

South Asian (SAS)

AF:

0.0857

AC:

413

AN:

4818

European-Finnish (FIN)

AF:

0.0660

AC:

699

AN:

10588

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68008

Other (OTH)

AF:

0.0142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

237

356

474

593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00688

Hom.:

Bravo

AF:

0.0117

ESP6500AA

AF:

0.0139

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.0265

AC:

3213

Asia WGS

AF:

0.0750

AC:

259

AN:

3476

EpiCase

AF:

0.00218

EpiControl

AF:

0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Feb 17, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYLK c.2533C>T (p.Arg845Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.027 in 246212 control chromosomes in the gnomAD database, including 240 homozygotes. The observed variant frequency is approximately 1080-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2533C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Dec 06, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg845Cys in exon 18 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 1.4% (61/4402) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs3732485). -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 7

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Jan 23, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

Feb 01, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aortic aneurysm, familial thoracic 6

Benign:1

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.23

.;.;.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.78

.;T;T;T;.;.

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;N;N;.;N

PhyloP100

-0.049

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.58

N;.;N;N;N;N

REVEL

Benign

0.062

Sift

Benign

0.25

T;.;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.021

B;B;B;B;B;B

Vest4

0.083

MPC

0.22

ClinPred

0.0016

GERP RS

1.3

PromoterAI

-0.057

Neutral

(source)

Varity_R

0.048

gMVP

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over