rs149078011

Positions:

Variant summary

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

The NM_000432.4(MYL2):c.459G>C(p.Lys153Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K153E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

MYL2
NM_000432.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.734

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000432.4

BP4

Computational evidence support a benign effect (MetaRNN=0.3010088).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYL2	NM_000432.4 linkuse as main transcript	c.459G>C	p.Lys153Asn	missense_variant	7/7	ENST00000228841.15
MYL2	NM_001406745.1 linkuse as main transcript	c.417G>C	p.Lys139Asn	missense_variant	6/6
MYL2	NM_001406916.1 linkuse as main transcript	c.402G>C	p.Lys134Asn	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MYL2	ENST00000228841.15 linkuse as main transcript	c.459G>C	p.Lys153Asn	missense_variant	7/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1 linkuse as main transcript	c.417G>C	p.Lys139Asn	missense_variant	6/6	3
MYL2	ENST00000663220.1 linkuse as main transcript	c.402G>C	p.Lys134Asn	missense_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249336

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

134944

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461136

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151868

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 21, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2021	Variant summary: MYL2 c.459G>C (p.Lys153Asn) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) positioned in the last exon of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249336 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.459G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (examples: Bick_2012, Walsh_2017, and Ho_2018). These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 153 of the MYL2 protein (p.Lys153Asn). This variant is present in population databases (rs149078011, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30297972). ClinVar contains an entry for this variant (Variation ID: 43478). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 15, 2023

This missense variant replaces lysine with asparagine at codon 153 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 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 30297972). This variant has been identified in 10/280724 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2023

Reported in patients with HCM in published literature (Walsh et al., 2017; Ho et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 22958901, 30297972) -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2020

The c.459G>C (p.K153N) alteration is located in exon 7 (coding exon 7) of the MYL2 gene. This alteration results from a G to C substitution at nucleotide position 459, causing the lysine (K) at amino acid position 153 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

CardioboostCm

Uncertain

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

D;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.28

Sift

Benign

0.091

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0070

B;.

Vest4

0.29

MutPred

0.39

Loss of methylation at K153 (P = 0.013);.;

MVP

0.87

MPC

0.48

ClinPred

0.12

GERP RS

3.1

Varity_R

0.43

gMVP

0.68

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

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