3-123732926-G-C

Variant names:

• chr3-123732926-G-C
• rs9833275
• NM_053025.4:c.1486C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.1486C>G​(p.Leu496Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,614,178 control chromosomes in the GnomAD database, including 806,722 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L496A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 1.0 (75947 hom., cov: 32)
  • Exomes 𝑓: 1.0 (730775 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.43
• Publications: 28 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1043314E-6).
• BP6: Variant 3-123732926-G-C is Benign according to our data. Variant chr3-123732926-G-C is described in ClinVar as Benign. ClinVar VariationId is 226755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.1486C>G	p.Leu496Val	missense	Exon 11 of 34	NP_444253.3
	MYLK	NM_053027.4		c.1486C>G	p.Leu496Val	missense	Exon 11 of 33	NP_444255.3
	MYLK	NM_001321309.2		c.958C>G	p.Leu320Val	missense	Exon 10 of 33	NP_001308238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.1486C>G	p.Leu496Val	missense	Exon 11 of 34	ENSP00000353452.3
	MYLK	ENST00000464489.5	TSL:1	n.*1065C>G		non_coding_transcript_exon	Exon 10 of 33	ENSP00000417798.1
	MYLK	ENST00000464489.5	TSL:1	n.*1065C>G		3_prime_UTR	Exon 10 of 33	ENSP00000417798.1

Frequencies

GnomAD3 genomes AF: 0.999 AC: 151979 AN: 152184 Hom.: 75888 Cov.: 32

Gnomad AFR AF: 0.995

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.999

GnomAD2 exomes AF: 1.00 AC: 251311 AN: 251386 AF XY: 1.00

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1461713 AN: 1461876 Hom.: 730775 Cov.: 62 AF XY: 1.00 AC XY: 727175 AN XY: 727244

African (AFR) AF: 0.996 AC: 33331 AN: 33480

American (AMR) AF: 1.00 AC: 44719 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86257 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53420 AN: 53420

Middle Eastern (MID) AF: 1.00 AC: 5756 AN: 5756

European-Non Finnish (NFE) AF: 1.00 AC: 1112007 AN: 1112008

Other (OTH) AF: 1.00 AC: 60387 AN: 60394

GnomAD4 genome AF: 0.999 AC: 152097 AN: 152302 Hom.: 75947 Cov.: 32 AF XY: 0.999 AC XY: 74353 AN XY: 74454

African (AFR) AF: 0.995 AC: 41376 AN: 41576

American (AMR) AF: 1.00 AC: 15306 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 1.00 AC: 4814 AN: 4814

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68030 AN: 68030

Other (OTH) AF: 0.999 AC: 2113 AN: 2116

Alfa AF: 0.935 Hom.: 52009

Bravo AF: 0.999

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.996 AC: 4388

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 1.00 AC: 121366

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

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

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

Leu496Val in exon 11 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 100.0% (362/362) of mixed American ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs9833275).

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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.

Aortic aneurysm, familial thoracic 7 Benign:5

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

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

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

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Jan 25, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2014

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.065	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.50	N
PhyloP100		2.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.93	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.36
ClinPred		0.020	T
GERP RS		5.3
Varity_R		0.31
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9833275; hg19: chr3-123451773; COSMIC: COSV104664126; COSMIC: COSV104664126;