rs12172926

Variant names:

• chr3-123700441-C-T
• rs12172926
• NM_053025.4:c.3027G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_053025.4(MYLK):​c.3027G>A​(p.Glu1009Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,609,724 control chromosomes in the GnomAD database, including 6,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (875 hom., cov: 30)
  • Exomes 𝑓: 0.036 (5882 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.159
• Publications: 9 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-AS1 (HGNC:42440): (MYLK antisense RNA 1)

LOC105369194 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-123700441-C-T is Benign according to our data. Variant chr3-123700441-C-T is described in ClinVar as Benign. ClinVar VariationId is 194902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.159 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.3027G>A	p.Glu1009Glu	synonymous_variant	Exon 18 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.3027G>A	p.Glu1009Glu	synonymous_variant	Exon 18 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8187 AN: 151634 Hom.: 869 Cov.: 30

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0476

GnomAD2 exomes AF: 0.0727 AC: 18166 AN: 249944 AF XY: 0.0741

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.506

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0364 AC: 53006 AN: 1457972 Hom.: 5882 Cov.: 40 AF XY: 0.0394 AC XY: 28554 AN XY: 724660

African (AFR) AF: 0.0846 AC: 2811 AN: 33240

American (AMR) AF: 0.0215 AC: 954 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 300 AN: 26024

East Asian (EAS) AF: 0.441 AC: 17474 AN: 39630

South Asian (SAS) AF: 0.156 AC: 13407 AN: 85968

European-Finnish (FIN) AF: 0.0179 AC: 957 AN: 53352

Middle Eastern (MID) AF: 0.0212 AC: 122 AN: 5748

European-Non Finnish (NFE) AF: 0.0121 AC: 13430 AN: 1109472

Other (OTH) AF: 0.0590 AC: 3551 AN: 60174

GnomAD4 genome AF: 0.0541 AC: 8215 AN: 151752 Hom.: 875 Cov.: 30 AF XY: 0.0574 AC XY: 4254 AN XY: 74160

African (AFR) AF: 0.0825 AC: 3410 AN: 41348

American (AMR) AF: 0.0266 AC: 406 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.479 AC: 2416 AN: 5048

South Asian (SAS) AF: 0.180 AC: 864 AN: 4794

European-Finnish (FIN) AF: 0.0165 AC: 174 AN: 10572

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 786 AN: 67954

Other (OTH) AF: 0.0529 AC: 111 AN: 2100

Alfa AF: 0.0288 Hom.: 1264

Bravo AF: 0.0576

Asia WGS AF: 0.314 AC: 1089 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu1009Glu in exon 18 of MYLK: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and has been identif ied in 51% (4359/8640) of East Asian chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs12172926). -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 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. -

not provided Benign:2

Nov 25, 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:1

Feb 19, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.37
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12172926; hg19: chr3-123419288; COSMIC: COSV60609414; COSMIC: COSV60609414;