12-110913118-G-T

Position:

• chr12-110913118-G-T

Variant summary

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

The NM_000432.4(MYL2):​c.380C>A​(p.Ala127Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A127V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14

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 53 pathogenic changes around while only 9 benign (85%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.380C>A	p.Ala127Glu	missense_variant	6/7	ENST00000228841.15
MYL2	NM_001406745.1	c.338C>A	p.Ala113Glu	missense_variant	5/6
MYL2	NM_001406916.1	c.323C>A	p.Ala108Glu	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.380C>A	p.Ala127Glu	missense_variant	6/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.338C>A	p.Ala113Glu	missense_variant	5/6	3
MYL2	ENST00000663220.1	c.323C>A	p.Ala108Glu	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.45
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.78	D;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.037	D;T
Polyphen		0.015	B;.
Vest4		0.45
MutPred		0.56		Gain of disorder (P = 0.023);.;
MVP		0.88
MPC		0.61
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.70
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: rs141878747; hg19: chr12-111350922; COSMIC: COSV99960773; COSMIC: COSV99960773;