rs727504300

Variant names:

• chr12-110919151-TG-A
• rs727504300
• NM_000432.4:c.45_46delCAinsT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP2

The NM_000432.4(MYL2):​c.45_46delCAinsT​(p.Asn16ThrfsTer34) variant causes a frameshift, 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S15S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 frameshift, missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.76
• Publications: 0 publications found

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]

MYL2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 31 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39564 (below the threshold of 3.09). Trascript score misZ: 1.1124 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 10, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, congenital fiber-type disproportion myopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.45_46delCAinsT	p.Asn16ThrfsTer34	frameshift_variant, missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.45_46delCAinsT	p.Asn16ThrfsTer27	frameshift_variant, missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.-13_-12delCAinsT		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.45_46delCAinsT	p.Asn16ThrfsTer34	frameshift_variant, missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 08, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asn16fs v ariant in MYL2 has been identified by our laboratory in 1 individual with HCM. I t has also been identified in 1/66542 European chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 16 and leads to a premature termination codon 34 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . However, loss of function is not an established disease mechanism for this gen e at this time. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Asn16fs variant is uncertain. -

Hypertrophic cardiomyopathy 10 Uncertain:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn16Thrfs*34) in the MYL2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYL2 cause disease. This variant is present in population databases (rs781431079, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 1359362). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Jun 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.45_46delCAinsT variant, located in coding exon 2 of the MYL2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.N16Tfs*34). This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Walsh R et al. Genet Med, 2017 Feb;19:192-203). Although biallelic loss of function of MYL2 has been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency of MYL2 has not been established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant MYL2-related cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=9/191	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504300; hg19: chr12-111356955;