20-31819584-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_033118.4(MYLK2):c.4G>A(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,551,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 3.56

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012375087).
• BP6: Variant 20-31819584-G-A is Benign according to our data. Variant chr20-31819584-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46526.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2, Benign=1}. Variant chr20-31819584-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 214 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.4G>A	p.Ala2Thr	missense_variant	2/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.4G>A	p.Ala2Thr	missense_variant	2/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.4G>A	p.Ala2Thr	missense_variant	1/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000831 AC: 130 AN: 156500 Hom.: 0 AF XY: 0.000814 AC XY: 67 AN XY: 82336

Gnomad AFR exome AF: 0.000229

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.000846

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.00185 AC: 2592 AN: 1399266 Hom.: 1 Cov.: 31 AF XY: 0.00181 AC XY: 1247 AN XY: 690128

Gnomad4 AFR exome AF: 0.000380

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.000896

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74478

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00214 Hom.: 2

Bravo AF: 0.00140

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00156 AC: 12

ExAC AF: 0.000391 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	This variant is associated with the following publications: (PMID: 25188385, 26595808, 23861362, 26423924, 24503780) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYLK2: BS1 -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 10, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Ala2Thr varia nt in MYLK2 has been identified by our laboratory in 1 adult with DCM, 1 adult w ith HCM, 1 child with biventricular hypertrophy and dysfunction, and 1 child wit h possible LVNC/DCM who also carried a pathogenic variant in MYH7. The p.Ala2Thr variant has also been identified in 0.2% (143/72280) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSN P rs117502839). Arginine (Arg) at position 2 is not conserved in mice, which car ry a threonine (Thr) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide stron g support for or against an impact to the protein. In summary, while the clinic al significance of the p.Ala2Thr variant is uncertain, its frequency and lack of conservation in mice suggest that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2022	- -

Hypertrophic cardiomyopathy 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

MYLK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 31, 2020

- -

Long QT syndrome;C0042514:Ventricular tachycardia;C0878544:Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.061
Sift	Benign	0.12	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0050	B;B
Vest4		0.22
MVP		0.71
MPC		0.46
ClinPred		0.025	T
GERP RS		2.5
Varity_R		0.035
gMVP		0.11

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

Other links and lift over

dbSNP: rs117502839; hg19: chr20-30407387; COSMIC: COSV99057734;