rs376506450

Positions:

• chr12-110914244-C-G
• chr12-110914244-C-T

Variant summary

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

The NM_000432.4(MYL2):​c.216G>C​(p.Glu72Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E72E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.620

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.216G>C	p.Glu72Asp	missense_variant	4/7	ENST00000228841.15
MYL2	NM_001406745.1	c.174G>C	p.Glu58Asp	missense_variant	3/6
MYL2	NM_001406916.1	c.159G>C	p.Glu53Asp	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.216G>C	p.Glu72Asp	missense_variant	4/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.174G>C	p.Glu58Asp	missense_variant	3/6	3
MYL2	ENST00000663220.1	c.159G>C	p.Glu53Asp	missense_variant	4/7
MYL2	ENST00000549029.1	n.47G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 04, 2023

This missense variant replaces glutamic acid with aspartic acid at codon 72 of the MYL2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYL2-related 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	0.41
CardioboostCm	Uncertain	0.68
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.067	T;T
Polyphen		0.63	P;.
Vest4		0.61
MutPred		0.57		Gain of catalytic residue at G75 (P = 0.0117);.;
MVP		0.79
MPC		0.36
ClinPred		0.92	D
GERP RS		0.33
Varity_R		0.61
gMVP		0.78

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: rs376506450; hg19: chr12-111352048;