12-110913139-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1PM5BP4_ModerateBS1_SupportingBS2

The NM_000432.4(MYL2):c.359G>A(p.Arg120Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R120W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

MYL2
NM_000432.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 1.98

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 chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000432.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-110913140-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.19394654).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000854 (13/152306) while in subpopulation AMR AF= 0.000392 (6/15298). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4 link	c.359G>A	p.Arg120Gln	missense_variant	Exon 6 of 7	ENST00000228841.15	NP_000423.2	P10916Q6IB42
MYL2	NM_001406745.1 link	c.317G>A	p.Arg106Gln	missense_variant	Exon 5 of 6		NP_001393674.1
MYL2	NM_001406916.1 link	c.302G>A	p.Arg101Gln	missense_variant	Exon 6 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYL2	ENST00000228841.15 link	c.359G>A	p.Arg120Gln	missense_variant	Exon 6 of 7	1	NM_000432.4	ENSP00000228841.8	P10916
MYL2	ENST00000548438.1 link	c.317G>A	p.Arg106Gln	missense_variant	Exon 5 of 6	3		ENSP00000447154.1	G3V1V8
MYL2	ENST00000663220.1 link	c.302G>A	p.Arg101Gln	missense_variant	Exon 6 of 7			ENSP00000499568.1	A0A590UJU8
MYL2	ENST00000549029.1 link	n.291G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251486

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Dec 29, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 120 of the MYL2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with restrictive cardiomyopathy (PMID: 22260945). This variant has been identified in 16/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

not specified

Uncertain:1

Jul 14, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 10

Uncertain:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 120 of the MYL2 protein (p.Arg120Gln). This variant is present in population databases (rs192057022, gnomAD 0.02%). This missense change has been observed in individual(s) with restrictive cardiomyopathy, hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 22260945, 36264615, 38540378). ClinVar contains an entry for this variant (Variation ID: 36645). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not provided

Uncertain:1

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

Aug 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Oct 02, 2015

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1

Sep 17, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 120 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with restrictive cardiomyopathy (PMID: 22260945). This variant has been identified in 16/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Cardiovascular phenotype

Benign:1

Mar 24, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Benign

0.14

CardioboostCm

Benign

0.083

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.94

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.093

T;T

Sift4G

Uncertain

0.052

T;T

Polyphen

0.70

P;.

Vest4

0.18

MVP

0.85

MPC

0.57

ClinPred

0.12

GERP RS

-0.34

Varity_R

0.090

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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