rs397516409

Positions:

• chr12-110919115-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 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. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain EF-hand 1 (size 35) in uniprot entity MLRV_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.82G>A	p.Glu28Lys	missense_variant	2/7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.82G>A	p.Glu28Lys	missense_variant	2/6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.25G>A	p.Glu9Lys	missense_variant	2/7			ENSP00000499568.1
MYL2	ENST00000546404.1	c.82G>A	p.Glu28Lys	missense_variant	2/2	2		ENSP00000499645.1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2012

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;.
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

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

Other links and lift over

dbSNP: rs397516409; hg19: chr12-111356919;