3-123682213-C-T

Variant names:

Variant summary

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

The ENST00000504946.6(MYLK):c.1272G>A(p.Ser424Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,590,224 control chromosomes in the GnomAD database, including 1,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 109 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1518 hom. )

Consequence

MYLK
ENST00000504946.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.767

Publications

5 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:

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=-0.74).

BP6

Variant 3-123682213-C-T is Benign according to our data. Variant chr3-123682213-C-T is described in ClinVar as Benign. ClinVar VariationId is 226765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0323 (4914/152190) while in subpopulation NFE AF = 0.0465 (3163/67996). AF 95% confidence interval is 0.0452. There are 109 homozygotes in GnomAd4. There are 2466 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 109 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.3652+11G>A		intron_variant	Intron 20 of 33	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 link	c.3652+11G>A		intron_variant	Intron 20 of 33	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4916

AN:

152072

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00835

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0211

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0266

Gnomad FIN

AF:

0.0700

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0248

GnomAD2 exomes

AF:

0.0339

AC:

7349

AN:

216504

AF XY:

0.0349

show subpopulations

Gnomad AFR exome

AF:

0.00725

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000306

Gnomad FIN exome

AF:

0.0650

Gnomad NFE exome

AF:

0.0447

Gnomad OTH exome

AF:

0.0373

GnomAD4 exome

AF:

0.0429

AC:

61665

AN:

1438034

Hom.:

1518

Cov.:

AF XY:

0.0429

AC XY:

30573

AN XY:

712922

show subpopulations

African (AFR)

AF:

0.00595

AC:

198

AN:

33250

American (AMR)

AF:

0.0158

AC:

653

AN:

41208

Ashkenazi Jewish (ASJ)

AF:

0.0252

AC:

645

AN:

25580

East Asian (EAS)

AF:

0.000179

AC:

AN:

39204

South Asian (SAS)

AF:

0.0297

AC:

2445

AN:

82408

European-Finnish (FIN)

AF:

0.0620

AC:

3230

AN:

52086

Middle Eastern (MID)

AF:

0.0178

AC:

102

AN:

5732

European-Non Finnish (NFE)

AF:

0.0474

AC:

52138

AN:

1098950

Other (OTH)

AF:

0.0377

AC:

2247

AN:

59616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2567

5134

7702

10269

12836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1918

3836

5754

7672

9590

<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:

0.0323

AC:

4914

AN:

152190

Hom.:

109

Cov.:

AF XY:

0.0332

AC XY:

2466

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00833

AC:

346

AN:

41538

American (AMR)

AF:

0.0211

AC:

323

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0268

AC:

129

AN:

4808

European-Finnish (FIN)

AF:

0.0700

AC:

741

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0465

AC:

3163

AN:

67996

Other (OTH)

AF:

0.0246

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

246

492

738

984

1230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0389

Hom.:

Bravo

AF:

0.0275

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

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

3652+11G>A in intron 20 of MYLK: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 4.5% (386/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs41271437). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 19, 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.3652+11G>A 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 0.034 in 247866 control chromosomes in the gnomAD database, including 191 homozygotes. The observed variant frequency is approximately 1366-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. Two ClinVar submissions (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

9.8

(source)

DANN

Benign

0.75

PhyloP100

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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