12-110919166-C-G

Variant names:

• chr12-110919166-C-G
• rs397516402
• NM_000432.4:c.31G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000432.4(MYL2):​c.31G>C​(p.Gly11Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G11G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83

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 2 ACMG points.

• PM1: In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 55 pathogenic changes around while only 9 benign (86%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22816485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.31G>C	p.Gly11Arg	missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.31G>C	p.Gly11Arg	missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.-27G>C		5_prime_UTR_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.31G>C	p.Gly11Arg	missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.31G>C	p.Gly11Arg	missense_variant	Exon 2 of 6	3		ENSP00000447154.1
MYL2	ENST00000546404.1	c.31G>C	p.Gly11Arg	missense_variant	Exon 2 of 2	2		ENSP00000499645.1
MYL2	ENST00000663220.1	c.-27G>C		5_prime_UTR_variant	Exon 2 of 7			ENSP00000499568.1

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

Cardiomyopathy Uncertain:1

Mar 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 11 of the MYL2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
CardioboostCm	Benign	0.029
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.70
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.55	N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.23
Sift	Benign	0.13	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.013	B;.
Vest4		0.36
MutPred		0.32		Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);
MVP		0.88
MPC		0.47
ClinPred		0.76	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.40

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: rs397516402; hg19: chr12-111356970;