rs41293104

chr20-31823538-T-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.834T>A(p.Asn278Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,613,908 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: -2.77

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=0.018444955).
• BP6: Variant 20-31823538-T-A is Benign according to our data. Variant chr20-31823538-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191740.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr20-31823538-T-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 66 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.834T>A	p.Asn278Lys	missense_variant	5/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.834T>A	p.Asn278Lys	missense_variant	5/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.834T>A	p.Asn278Lys	missense_variant	4/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251186 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135790

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000588 AC: 859 AN: 1461588 Hom.: 2 Cov.: 31 AF XY: 0.000550 AC XY: 400 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000750

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74474

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 26, 2015	The p.Asn278Lys variant in MYLK2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 34/66410 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41293104). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Asn278Lys variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2021	Variant summary: MYLK2 c.834T>A (p.Asn278Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 282572 control chromosomes, predominantly at a frequency of 0.00057 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.834T>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:1

Uncertain significance, 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	Feb 18, 2020	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 191740; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362) -

Hypertrophic cardiomyopathy 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2019	- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 29, 2016

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 26, 2017

- -

MYLK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.022
Dann	Benign	0.28
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.068	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.10
Sift	Benign	0.11	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0020	B;B
Vest4		0.33
MutPred		0.25		Gain of ubiquitination at N278 (P = 0.0162);Gain of ubiquitination at N278 (P = 0.0162);
MVP		0.42
MPC		0.14
ClinPred		0.019	T
GERP RS		-4.8
Varity_R		0.12
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41293104; hg19: chr20-30411341;