NM_053025.4:c.62C>A

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.62C>A(p.Pro21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,450 control chromosomes in the GnomAD database, including 13,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. P21S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.17 ( 3409 hom., cov: 32)

Exomes 𝑓: 0.10 ( 10153 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.192

Publications

43 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 Gene-Disease associations (from GenCC):

aortic aneurysm, familial thoracic 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
megacystis-microcolon-intestinal hypoperistalsis syndrome 1
Inheritance: AR Classification: STRONG Submitted by: G2P
connective tissue disorder
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
megacystis-microcolon-intestinal hypoperistalsis syndrome
Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

MYLK 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=0.005610466).

BP6

Variant 3-123793780-G-T is Benign according to our data. Variant chr3-123793780-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.62C>A	p.Pro21His	missense_variant	Exon 4 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 link	c.62C>A	p.Pro21His	missense_variant	Exon 4 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25753

AN:

151480

Hom.:

3395

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.142

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.0667

Gnomad SAS

AF:

0.210

Gnomad FIN

AF:

0.0430

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0874

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.118

AC:

29719

AN:

251342

AF XY:

0.119

show subpopulations

Gnomad AFR exome

AF:

0.376

Gnomad AMR exome

AF:

0.0704

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.0661

Gnomad FIN exome

AF:

0.0502

Gnomad NFE exome

AF:

0.0894

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.103

AC:

150124

AN:

1461852

Hom.:

10153

Cov.:

AF XY:

0.105

AC XY:

76213

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.389

AC:

13038

AN:

33480

American (AMR)

AF:

0.0745

AC:

3331

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4704

AN:

26134

East Asian (EAS)

AF:

0.0677

AC:

2689

AN:

39698

South Asian (SAS)

AF:

0.201

AC:

17379

AN:

86254

European-Finnish (FIN)

AF:

0.0527

AC:

2814

AN:

53418

Middle Eastern (MID)

AF:

0.137

AC:

788

AN:

5768

European-Non Finnish (NFE)

AF:

0.0879

AC:

97770

AN:

1111984

Other (OTH)

AF:

0.126

AC:

7611

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

7840

15680

23519

31359

39199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3846

7692

11538

15384

19230

<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:

0.170

AC:

25818

AN:

151598

Hom.:

3409

Cov.:

AF XY:

0.167

AC XY:

12410

AN XY:

74122

show subpopulations

African (AFR)

AF:

0.375

AC:

15483

AN:

41322

American (AMR)

AF:

0.100

AC:

1528

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

579

AN:

3454

East Asian (EAS)

AF:

0.0662

AC:

339

AN:

5118

South Asian (SAS)

AF:

0.210

AC:

1007

AN:

4794

European-Finnish (FIN)

AF:

0.0430

AC:

455

AN:

10582

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0874

AC:

5923

AN:

67794

Other (OTH)

AF:

0.162

AC:

340

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

984

1968

2953

3937

4921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.114

Hom.:

5153

Bravo

AF:

0.181

TwinsUK

AF:

0.0860

AC:

319

ALSPAC

AF:

0.0843

AC:

325

ESP6500AA

AF:

0.363

AC:

1598

ESP6500EA

AF:

0.0938

AC:

807

ExAC

AF:

0.126

AC:

15333

Asia WGS

AF:

0.212

AC:

739

AN:

3478

EpiCase

AF:

0.0953

EpiControl

AF:

0.0920

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Dec 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.62C>A (p.Pro21His) in exon 4 of MYLK: This variant is not expected to have cli nical significance because it does not alter an amino acid residue and is not lo cated within the splice consensus sequence. It has been identified in 9% (807/86 00) of European American chromosomes and 36% (1598/4406) of African American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs28497577).

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1

Aug 24, 2020

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

Significance:Likely 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

Sep 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aortic aneurysm, familial thoracic 7

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 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.

not provided

Benign:2

Nov 26, 2024

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

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 29, 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.9

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0

.;.;.;T;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.0

.;T;T;T;.;.

MetaRNN

Benign

0.0056

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.26

N;N;N;N;N;N

PhyloP100

-0.19

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.23

N;.;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.47

T;.;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T

Vest4

0.11

ClinPred

0.011

GERP RS

0.15

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.076

gMVP

0.27

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