rs727505071

chr12-110913109-A-C

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.389T>G(p.Phe130Cys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F130Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.90

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 3 (size 35) in uniprot entity MLRV_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.389T>G	p.Phe130Cys	missense_variant	6/7	ENST00000228841.15
MYL2	NM_001406745.1	c.347T>G	p.Phe116Cys	missense_variant	5/6
MYL2	NM_001406916.1	c.332T>G	p.Phe111Cys	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.389T>G	p.Phe130Cys	missense_variant	6/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.347T>G	p.Phe116Cys	missense_variant	5/6	3
MYL2	ENST00000663220.1	c.332T>G	p.Phe111Cys	missense_variant	6/7
MYL2	ENST00000549029.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Dec 08, 2017

The p.Phe130Cys variant in MYL2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Phenylalanine (Phe) at posit ion 130 is highly conserved in mammals and across evolutionarily distant species and the change to Phenylalanine (Phe) was predicted to be pathogenic using a co mputational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, the clinical significance of the p.Phe130Cys variant is uncertain. ACMG/AMP Cri teria applied: PM2; PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.48		Gain of ubiquitination at K132 (P = 0.0856);.;
MVP		0.96
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.89

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: rs727505071; hg19: chr12-111350913;