rs9840993

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.439C>T(p.Pro147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,613,666 control chromosomes in the GnomAD database, including 762,095 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 Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 61300 hom., cov: 31)

Exomes 𝑓: 0.98 ( 700795 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.16

Publications

48 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=6.1008615E-7).

BP6

Variant 3-123739046-G-A is Benign according to our data. Variant chr3-123739046-G-A is described in ClinVar as Benign. ClinVar VariationId is 198606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.439C>T	p.Pro147Ser	missense_variant	Exon 7 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.439C>T	p.Pro147Ser	missense_variant	Exon 7 of 34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.885

AC:

134504

AN:

151972

Hom.:

61294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.642

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.943

Gnomad ASJ

AF:

0.966

Gnomad EAS

AF:

0.938

Gnomad SAS

AF:

0.922

Gnomad FIN

AF:

0.962

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.995

Gnomad OTH

AF:

0.905

GnomAD2 exomes

AF:

0.948

AC:

237916

AN:

250870

AF XY:

0.954

show subpopulations

Gnomad AFR exome

AF:

0.632

Gnomad AMR exome

AF:

0.951

Gnomad ASJ exome

AF:

0.966

Gnomad EAS exome

AF:

0.937

Gnomad FIN exome

AF:

0.969

Gnomad NFE exome

AF:

0.994

Gnomad OTH exome

AF:

0.966

GnomAD4 exome

AF:

0.977

AC:

1428507

AN:

1461576

Hom.:

700795

Cov.:

AF XY:

0.977

AC XY:

710333

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.624

AC:

20876

AN:

33474

American (AMR)

AF:

0.949

AC:

42414

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

25145

AN:

26120

East Asian (EAS)

AF:

0.938

AC:

37252

AN:

39696

South Asian (SAS)

AF:

0.928

AC:

79915

AN:

86120

European-Finnish (FIN)

AF:

0.973

AC:

51985

AN:

53404

Middle Eastern (MID)

AF:

0.960

AC:

5537

AN:

5768

European-Non Finnish (NFE)

AF:

0.996

AC:

1107640

AN:

1111926

Other (OTH)

AF:

0.956

AC:

57743

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1759

3517

5276

7034

8793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21624

43248

64872

86496

108120

<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:

0.885

AC:

134547

AN:

152090

Hom.:

61300

Cov.:

AF XY:

0.886

AC XY:

65882

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.641

AC:

26548

AN:

41418

American (AMR)

AF:

0.943

AC:

14435

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.966

AC:

3354

AN:

3472

East Asian (EAS)

AF:

0.938

AC:

4820

AN:

5136

South Asian (SAS)

AF:

0.922

AC:

4437

AN:

4814

European-Finnish (FIN)

AF:

0.962

AC:

10205

AN:

10606

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.995

AC:

67651

AN:

68022

Other (OTH)

AF:

0.903

AC:

1911

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

617

1234

1852

2469

3086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.963

Hom.:

252736

Bravo

AF:

0.872

TwinsUK

AF:

0.996

AC:

3694

ALSPAC

AF:

0.997

AC:

3844

ESP6500AA

AF:

0.637

AC:

2808

ESP6500EA

AF:

0.993

AC:

8539

ExAC

AF:

0.944

AC:

114556

Asia WGS

AF:

0.890

AC:

3094

AN:

3478

EpiCase

AF:

0.993

EpiControl

AF:

0.993

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Dec 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.439C) is the minor allele. This al lele (C) has been identified in 0.7% (61/8600) of European American chromosomes and 36% (1598/4406) of African American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs9840993) and thus meets cr iteria to be classified as benign. -

May 22, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 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. -

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, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 7

Benign:4

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 27, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 12, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: This c.439C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant was found in 114076/120782 control chromosomes from ExAC at a frequency of 0.9444785, which is more than 75557 times greater than the maximal expected frequency of a pathogenic allele (0.0000125) in this gene. This proves that this variant is a very common polymorphism. One clinical lab (via ClinVar) has classified this variant as benign. Taken together, this variant has been classified as Benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Aug 07, 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. -

Megacystis, microcolon, hypoperistalsis syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.29

.;.;.;T;.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.85

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.75

.;T;T;T;.;.

MetaRNN

Benign

6.1e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

L;L;L;L;L;L

PhyloP100

3.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

N;.;N;N;N;N

REVEL

Benign

0.088

Sift

Benign

0.29

T;.;T;T;T;T

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

0.095

B;B;B;B;B;B

Vest4

0.13

MPC

0.16

ClinPred

0.0077

GERP RS

1.3

Varity_R

0.037

gMVP

0.49

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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