12-110919139-T-G

Position:

• chr12-110919139-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000432.4(MYL2):​c.58A>C​(p.Met20Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.64

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 Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.58A>C	p.Met20Leu	missense_variant	2/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.58A>C	p.Met20Leu	missense_variant	2/6		NP_001393674.1
MYL2	NM_001406916.1	c.1A>C	p.Met1?	initiator_codon_variant	2/7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.58A>C	p.Met20Leu	missense_variant	2/7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.58A>C	p.Met20Leu	missense_variant	2/6	3		ENSP00000447154.1
MYL2	ENST00000546404.1	c.58A>C	p.Met20Leu	missense_variant	2/2	2		ENSP00000499645.1
MYL2	ENST00000663220.1	c.1A>C	p.Met1?	initiator_codon_variant	2/7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (MYL2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
CardioboostCm	Uncertain	0.68
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.084	T;D
Polyphen		0.0030	B;.
Vest4		0.66
MutPred		0.60		Gain of catalytic residue at N16 (P = 0.0112);Gain of catalytic residue at N16 (P = 0.0112);
MVP		0.81
MPC		0.41
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.73

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: rs199474816; hg19: chr12-111356943;