chr3-123682239-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_053025.4(MYLK):c.3637G>C(p.Val1213Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,601,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V1213V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8B:3

Conservation

PhyloP100: 0.402

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09415275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.3637G>C	p.Val1213Leu	missense_variant	Exon 20 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.3637G>C	p.Val1213Leu	missense_variant	Exon 20 of 34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000435

AC:

AN:

229728

Hom.:

AF XY:

0.0000325

AC XY:

AN XY:

123110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000141

AC:

204

AN:

1449174

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

106

AN XY:

719220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000179

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 28, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

not specified

Uncertain:2

Sep 11, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYLK c.3637G>C (p.Val1213Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 229728 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYLK causing Megacystis-Microcolon Hypoperistalsis Syndrome 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3637G>C in individuals affected with Megacystis-Microcolon Hypoperistalsis Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 568511). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jan 13, 2022

Phosphorus, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant results in an amino acid substitution of valine with leucine at codon 1213 of the MYLK gene. The variant has an entry in ClinVar (568511) NM_053025.4 (MYLK): c.3637G>C (p.Val1213Leu) and has occurred in GnomAD with a total MAF of 0.0040% and highest MAF of 0.0089% in the European population. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it benign, and SIFT tolerated, but no functional studies were performed to confirm this prediction. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance. -

Aortic aneurysm, familial thoracic 7

Uncertain:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1213 of the MYLK protein (p.Val1213Leu). This variant is present in population databases (rs368390254, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 568511). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 17, 2018

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYLK NM_053025.3 exon 20 p.Val1213Leu (c.3637G>C): This variant has not been reported in the literature and is present in 0.01% (11/116464) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-123401086-C-T). This variant amino acid Leucine (Leu) is present in 2 species (chinese hamster and golden hamster), and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Of note, another variant at the same amino acid residue position (p.Val1213Met) has been reported as being possibly associated with aortic dissections in a single individual (Wang et al. PMID: 21055718). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1

Uncertain:2

Oct 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYLK NM_053025.3 exon 20 p.Val1213Leu (c.3637G>C): This variant has not been reported in the literature and is present in 0.01% (11/116464) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-123401086-C-T). This variant is present in ClinVar (Variation ID:568511). This variant amino acid Leucine (Leu) is present in 2 species (chinese hamster and golden hamster), and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Of note, another variant at the same amino acid residue position (p.Val1213Met) has been reported as being possibly associated with aortic dissections in three individuals (Wang 2010 PMID: 21055718, Weerakkody 2018 PMID:29543232). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Nov 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1213L variant (also known as c.3637G>C), located in coding exon 17 of the MYLK gene, results from a G to C substitution at nucleotide position 3637. The valine at codon 1213 is replaced by leucine, an amino acid with highly similar properties. In addition, a different alteration at the same position, p.V1213M, has been detected in an individual with familial thoracic aortic aneurysm and dissection (TAAD) (Wang L et al. Am. J. Hum. Genet., 2010 Nov;87:701-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

.;.;.;T;.;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.78

.;T;T;T;.;.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.094

T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

L;.;L;L;.;L;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.60

N;.;N;N;N;N;N

REVEL

Benign

0.056

Sift

Benign

0.039

D;.;D;D;T;D;D

Sift4G

Uncertain

0.041

D;D;D;D;D;D;.

Polyphen

0.012

B;B;B;B;B;B;.

Vest4

0.19

MutPred

0.24

Gain of glycosylation at P1211 (P = 0.0828);.;Gain of glycosylation at P1211 (P = 0.0828);Gain of glycosylation at P1211 (P = 0.0828);.;Gain of glycosylation at P1211 (P = 0.0828);.;

MVP

0.69

MPC

0.18

ClinPred

0.060

GERP RS

2.8

Varity_R

0.044

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over