12-110915743-G-T

Position:

chr12-110915743-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The ENST00000228841.15(MYL2):c.141C>A(p.Asn47Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,614,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. N47Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

MYL2
ENST00000228841.15 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:16B:1O:1

Conservation

PhyloP100: -0.580

Variant links:

Genes affected

MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

MYL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain EF-hand 1 (size 35) in uniprot entity MLRV_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in ENST00000228841.15

BP4

Computational evidence support a benign effect (MetaRNN=0.33230838).

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYL2	NM_000432.4 linkuse as main transcript	c.141C>A	p.Asn47Lys	missense_variant	3/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406916.1 linkuse as main transcript	c.84C>A	p.Asn28Lys	missense_variant	3/7		NP_001393845.1
MYL2	NM_001406745.1 linkuse as main transcript	c.94-1419C>A		intron_variant			NP_001393674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYL2	ENST00000228841.15 linkuse as main transcript	c.141C>A	p.Asn47Lys	missense_variant	3/7	1	NM_000432.4	ENSP00000228841	P1
MYL2	ENST00000663220.1 linkuse as main transcript	c.84C>A	p.Asn28Lys	missense_variant	3/7			ENSP00000499568
MYL2	ENST00000548438.1 linkuse as main transcript	c.94-1419C>A		intron_variant		3		ENSP00000447154

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251444

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000577

AC:

843

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

369

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000685

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000276

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000408

Hom.:

Bravo

AF:

0.000249

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:16Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL2)	Mar 26, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2022	The MYL2 c.141C>A; p.Asn47Lys variant (rs199474808; ClinVar Variation ID: 31766) has been observed in at least two probands with hypertrophic cardiomyopathy; however, both we shown to harbor additional clinically suspicious variants in other genes associated with HCM (Andersen 2001, Hougs 2005, Berge 2014). It was also identified in a three month old child whose cause of death was ruled to be SIDS (Methner 2016). In vitro functional studies of the MYL2 p.Asn47Lys variant suggest it may impact MYL2 function; however, the exact in vivo consequences remain unclear at this time (Szczesna-Cordary 2004, Greenberg 2009, Greenberg 2010). Furthermore, this variant has been observed in many ostensibly healthy human populations (Amendola 2015, Andreasen 2013, Whiffin 2017), and is found in the non-Finnish European population with an allele frequency of 0.036% (46/129146 alleles) in the Genome Aggregation Database. The asparagine at codon 47 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.158). Due to conflicting information, the clinical significance of the p.Asn47Lys variant is uncertain at this time. References: Andreasen C et al. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet. 2013 Sep;21(9):918-28. PMID: 23299917 Andersen PS et al. Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. J Med Genet. 2001 Dec;38(12):E43. PMID: 11748309 Amendola LM et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 Mar;25(3):305-15. PMID: 25637381 Berge KE and Leren TP. Genetics of hypertrophic cardiomyopathy in Norway. Clin Genet. 2014 Oct;86(4):355-60. PMID: 24111713. Greenberg MJ et al. Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanics and kinetics. J Mol Cell Cardiol. 2009 Jan;46(1):108-15. PMID: 18929571 Greenberg MJ et al. Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17403-8. PMID: 20855589 Hougs L et al. One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations (corrected) in MYH7 rod region. Eur J Hum Genet. 2005 Feb;13(2):161-5 PMID: 15483641. Methner DN et al. Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. Genome Res. 2016 Sep;26(9):1170-7. PMID: 27435932 Szczesna-Cordary D et al. Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. J Biol Chem. 2004 Jan 30;279(5):3535-42. PMID: 14594949. Whiffin N et al. Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med. 2017 Oct;19(10):1151-1158. PMID: 28518168 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2024	Reported in patients with HCM and DCM in published literature; several patients harbored additional cardiogenetic variants (PMID: 11748309, 15483641, 24111713, 35653365, 34935411, 25351510); Identified in an infant with a history of apneic episodes who died at three months of age due to sudden infant death syndrome (SIDS) (PMID: 27435932); Several in vitro assays have demonstrated that p.(N47K) impairs myosin kinetics, and in vivo studies in transgenic mice have shown that p.(N47K) causes reduced cardiac function and hypertrophy; nevertheless, it is uncertain how these results might translate to the development of HCM in humans (PMID: 14594949, 16837010, 19150977, 18929571, 20855589, 26116789, 28467684); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 31104103, 23299917, 15483641, 14594949, 20855589, 24111713, 28301460, 28467684, 16837010, 19150977, 26116789, 26284228, 28518168, 30706179, 11102452, 12668451, 34797172, 37937776, 37652022, 35653365, 22958901, 31315475, 33337957, 35680059, 35345275, 33558530, 11748309, 27435932, 18929571, 34935411, 25351510, 21415409, 24842367) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Asn47Lys variant in MYL2 has been reported in 3 individuals with HCM (Andersen 2001, Hougs 2005, Alvarez-Acosta 2014) and has also been reported in ClinVar (Variation ID 31766). Clinvar: VUS (CSER, GeneDx, Invitae, Agnes Ginges, Blueprint), Path (HCIFS-Postmortem genetic screening project). This variant has also been identified by our laboratory in three Caucasian individuals (2 with HCM, and 1 with LVNC, hypotonia and motor delay), one of whom (with HCM) carried a second, likely pathogenic variant in another gene. In addition, the p.Asn47Lys variant has been identified in 48/126660 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199474808). Studies suggest that this variant may alter contraction function of cardiac cells (Szczesna-Cordary 2004, Abraham 2009, Greenberg 2009, Greenberg 2010). However, these in vitro assays may not accurately represent biological function. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). However, asparagine (Asn) at position 47 is not conserved in mammals and additional computational prediction tools suggest that the p.Asn47Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, due to the conflicting information currently available, additional data is needed to fully assess the clinical significance of the p.Asn47Lys variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2024	BS1, BS2_supporting, BP4, PS3_moderate, PS4_supporting -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 07, 2015	- -

Hypertrophic cardiomyopathy 10

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 23, 2022	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 47 of the MYL2 protein (p.Asn47Lys). This variant is present in population databases (rs199474808, gnomAD 0.04%). This missense change has been observed in individual(s) with MYL2-related conditions (PMID: 11748309, 24111713, 27435932). ClinVar contains an entry for this variant (Variation ID: 31766). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MYL2 function (PMID: 14594949, 18929571, 19150977, 20855589). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 55 heterozygotes, 0 homozygotes). (SP) 0308 - Population frequency for this variant is out of keeping with known incidence of hypertrophic cardiomyopathy. (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated calcium-binding site (PDB; PMID: 14594949). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been identified in HCM patients, both of whom also harboured another variant in a different gene. It was also reported in a case of sudden infant death syndrome and three offspring from the Framingham Heart Study, although their clinical status was not indicated. Within the VCGS cohort, it was reported in three HCM patients, one of whom had another VUS in DSP and the other two harbouring pathogenic variants in MYBPC3. Finally, this variant has been classified as a VUS by diagnostic laboratories in ClinVar (VCSG; ClinVar; PMID: 24111713, 11748309, 15483641, 27435932, 22958901). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrated impaired myosin kinetics and animal models recapitulated HCM phenotype (PMID: 28467684, 18929571, 20855589, 26116789). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This missense variant replaces asparagine with lysine at codon 47 of the MYL2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies in vitro and in transgenic animal models have shown that this variant causes a reduction in Ca2+ binding, an increase in Ca2+ sensitivity of myofibrillar ATPase activity, and in a reduction in force and power output (PMID: 14594949, 18929571, 19150977, 20855589, 31315475, 33558530). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11748309, 24111713, 25351510, 33558530) and in an individual affected with unexplained sudden death (PMID: 27435932). This variant also occurs at an appreciable frequency in the general population and has been identified in 55/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has also been found in individuals referred for cardiomyopathy genetic testing at a commercial laboratory, several of whom harbored other deleterious variants (ClinVar variation ID 31766). In summary, although experimental studies indicate this variant may have a deleterious impact on protein function, this variant has not been observed in a significant number of affected individuals and has not been shown to segregate with disease in family studies. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Death in infancy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Mar 27, 2015

- -

Premature ventricular contraction

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 11, 2014

- -

Hypertrophic cardiomyopathy 10;C5561937:Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 01, 2022

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

This missense variant replaces asparagine with lysine at codon 47 of the MYL2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. Experimental studies in vitro and in transgenic animal models have shown that this variant causes a reduction in Ca2+ binding, an increase in Ca2+ sensitivity of myofibrillar ATPase activity, and in a reduction in force and power output (PMID: 14594949, 18929571, 19150977, 20855589, 31315475, 33558530). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 11748309, 24111713, 25351510, 33558530, 38489124), in two individuals affected with dilated cardiomyopathy (PMID: 34935411, 37904629), and in one individual affected with unexplained sudden death (PMID: 27435932). This variant also occurs at an appreciable frequency in the general population and has been identified in 55/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has also been found in individuals referred for cardiomyopathy genetic testing at a commercial laboratory, several of whom harbored other deleterious variants (ClinVar variation ID 31766). In summary, although experimental studies indicate this variant may have a deleterious impact on protein function, this variant has not been observed in a significant number of affected individuals and has not been shown to segregate with disease in family studies. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 03, 2017

This MYL2 Asn47Lys variant has been identified in one published HCM proband with marked progression of hypertrophy over two years, and was absent from 150 controls (Anderson PS, et al., 2001). The proband was later found to be a carrier of second variant; MYH7 Arg1712Trp (Hougs L, et al., 2005). This variant has an allele frequency of 0.01% (22 alleles) in the Exome Aggregation Consortium population dataset (http://exac.broadinstitute.org/) which is more frequent than we would expect for an HCM causative variant. We have identified this variant in a HCM proband, who progressed to heart failure and consequently received a heart transplant. Computational tools SIFT and PolyPhen-2 predict the variant to be "tolerated" and "benign" respectively, however MutationTaster and PolyPhen-HCM predict this variant to be "disease-causing" and "pathogenic". Functional studies suggest this variant may impact contraction (Szczesna-Cordary D, et al., 2004)and force, particularly under loaded conditions (Abraham TP, et al., 2009; Greenberg MJ, et al., 2009; Greenberg MJ, et al., 2010). The variant was discussed at our multidisciplinary pathogenicity meeting and it was agreed based on current literature, and the greater than expected frequency in the ExAC dataset, that it should be considered a variant of "uncertain significance", though noted this may be downgraded in future. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

CardioboostCm

Benign

0.090

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.48

CADD

Benign

3.1

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.81

M_CAP

Benign

0.029

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.21

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.73

REVEL

Benign

0.16

Sift

Uncertain

0.017

Sift4G

Benign

0.25

Polyphen

0.31

Vest4

0.80

MutPred

0.55

Gain of ubiquitination at N47 (P = 0.0155);

MVP

0.62

MPC

0.64

ClinPred

0.069

GERP RS

-5.1

Varity_R

0.34

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over