rs55807353

chr20-31832010-G-Achr20-31832010-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_033118.4(MYLK2):c.1584G>A(p.Arg528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,609,828 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MYLK2 NM_033118.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0560

Genes affected

MYLK2 (HGNC:16243): (myosin light chain kinase 2) This gene encodes a myosin light chain kinase, a calcium/calmodulin dependent enzyme, that is exclusively expressed in adult skeletal muscle. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 20-31832010-G-A is Benign according to our data. Variant chr20-31832010-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-31832010-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.056 with no splicing effect.
• BS2: High AC in GnomAd at 180 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.1584G>A	p.Arg528=	synonymous_variant	12/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.1584G>A	p.Arg528=	synonymous_variant	12/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.1584G>A	p.Arg528=	synonymous_variant	11/12	1		P1
MYLK2	ENST00000468730.1	n.522G>A		non_coding_transcript_exon_variant	5/6	1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000818 AC: 197 AN: 240852 Hom.: 0 AF XY: 0.000921 AC XY: 120 AN XY: 130334

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000508

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00115 AC: 1676 AN: 1457504 Hom.: 4 Cov.: 35 AF XY: 0.00116 AC XY: 840 AN XY: 724766

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000477

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74484

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000839 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2022	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2015	p.Arg528Arg in exon 12 of MYLK2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.1% (54/52690) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs55807353). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2017	Variant summary: The MYLK2 c.1584G>A (p.Arg528Arg)causes a synonymous change involving the alteration of a non-conserved nucleotide, 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 80/94662 (1/1183), which is approximately 34 times the estimated maximal expected allele frequency for a pathogenic MYLK2 variant of 1/40000, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Therefore, the variant of interest has been classified as Benign. -

Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.8
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs55807353; hg19: chr20-30419813;