rs397516409

Variant names:

• chr12-110919115-C-T
• rs397516409
• NM_000432.4:c.82G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000432.4(MYL2):​c.82G>A​(p.Glu28Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging 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. E28D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39564 (below the threshold of 3.09). Trascript score misZ: 1.1124 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 10, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, congenital fiber-type disproportion myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.82G>A	p.Glu28Lys	missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.82G>A	p.Glu28Lys	missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.25G>A	p.Glu9Lys	missense_variant	Exon 2 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.82G>A	p.Glu28Lys	missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Glu28Lys va riant in MYL2 has not been reported in the literature nor previously identified in >2300 individuals (>1400 Caucasian) tested by our laboratory. This low freque ncy supports a pathogenic role. Glutamic acid (Glu) at position 28 is highly con served in mammals and across evolutionarily distant species and the change to Ly sine (Lys) was predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-est ablished clinical significance. This tool's pathogenic prediction is estimated t o be correct 94% of the time (Jordan 2011). Although this data suggests that the Glu28Lys variant may be pathogenic, additional studies are needed to fully asse ss its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.9	M;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.018	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.94	P;.
Vest4		0.94
MutPred		0.72		Gain of methylation at E28 (P = 0.0032);Gain of methylation at E28 (P = 0.0032);
MVP		0.94
MPC		0.93
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.93
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs397516409; hg19: chr12-111356919;