rs138877679

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_053025.4(MYLK):c.755-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,614,072 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 7 hom. )

Consequence

MYLK
NM_053025.4 intron

Scores

Splicing: ADA: 0.00004861

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0460

Publications

1 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 (BayesDel_noAF=-0.81).

BP6

Variant 3-123735428-G-A is Benign according to our data. Variant chr3-123735428-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 389625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0021 (320/152260) while in subpopulation AMR AF = 0.00425 (65/15300). AF 95% confidence interval is 0.00342. There are 3 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.755-12C>T		intron_variant	Intron 8 of 33	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.755-12C>T		intron_variant	Intron 8 of 33	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00197

AC:

495

AN:

251476

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00136

AC:

1983

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

1028

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33480

American (AMR)

AF:

0.00369

AC:

165

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

422

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000962

AC:

1070

AN:

1111962

Other (OTH)

AF:

0.00263

AC:

159

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00210

AC:

320

AN:

152260

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00284

AC:

118

AN:

41560

American (AMR)

AF:

0.00425

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000623

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68012

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00289

Hom.:

Bravo

AF:

0.00289

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 20, 2017

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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.755-12C>T in intron 8 of MYLK: This variant is not expected to have clinical significance because it does not cause the splice site sequence to diverge from consensus and it has been identified in 0.2% (183/121404) chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1388776 79). -

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

- -

Dec 16, 2019

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.755-12C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 251476 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 79-folds over 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.755-12C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant once as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign. -

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

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.2

(source)

DANN

Benign

0.65

PhyloP100

0.046

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.030

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