chr3-123722187-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_053025.4(MYLK):c.1745C>A(p.Thr582Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000154 in 1,562,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T582A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.96

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 3-123722187-G-T is Benign according to our data. Variant chr3-123722187-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409687.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.1745C>A	p.Thr582Asn	missense_variant	Exon 13 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.1745C>A	p.Thr582Asn	missense_variant	Exon 13 of 34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000353

AC:

AN:

169866

AF XY:

0.0000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1410528

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

696794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32268

American (AMR)

AF:

0.00

AC:

AN:

37498

Ashkenazi Jewish (ASJ)

AF:

0.000594

AC:

AN:

25246

East Asian (EAS)

AF:

0.00

AC:

AN:

36734

South Asian (SAS)

AF:

0.00

AC:

AN:

79860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1085300

Other (OTH)

AF:

0.000103

AC:

AN:

58448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000443

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 7

Uncertain:1Benign:1

Mar 30, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Apr 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jun 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T582N variant (also known as c.1745C>A), located in coding exon 10 of the MYLK gene, results from a C to A substitution at nucleotide position 1745. The threonine at codon 582 is replaced by asparagine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with aortic aneurysm/dilation (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

.;.;.;D;.;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

.;D;D;D;.;.

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.74

D;D;D;D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.1

M;.;M;M;.;M

PhyloP100

4.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

N;.;N;N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0050

D;.;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.65

MutPred

0.62

Gain of catalytic residue at T582 (P = 0.0056);.;Gain of catalytic residue at T582 (P = 0.0056);Gain of catalytic residue at T582 (P = 0.0056);.;Gain of catalytic residue at T582 (P = 0.0056);

MVP

0.90

MPC

0.18

ClinPred

0.47

GERP RS

4.4

Varity_R

0.57

gMVP

0.89

Mutation Taster

=50/50

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over