rs786205430

Variant names:

• chr12-110911146-AG-A
• rs786205430
• NM_000432.4:c.431delC

Your query was ambiguous. Multiple possible variants found:

• chr12-110911146-AG-A
• chr12-110911146-AG-AGG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_000432.4(MYL2):​c.431delC​(p.Pro144LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,544,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MYL2 NM_000432.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 9.55

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 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.431delC	p.Pro144LeufsTer3	frameshift_variant	Exon 7 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.389delC	p.Pro130LeufsTer3	frameshift_variant	Exon 6 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.374delC	p.Pro125LeufsTer3	frameshift_variant	Exon 7 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.431delC	p.Pro144LeufsTer3	frameshift_variant	Exon 7 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.389delC	p.Pro130LeufsTer3	frameshift_variant	Exon 6 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.374delC	p.Pro125LeufsTer3	frameshift_variant	Exon 7 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes AF: 0.00000681 AC: 1 AN: 146902 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248926 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 34 AN: 1398014 Hom.: 0 Cov.: 32 AF XY: 0.0000317 AC XY: 22 AN XY: 694344

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: 0.0000318

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000681 AC: 1 AN: 146902 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy Pathogenic:1

Aug 05, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypertrophic cardiomyopathy 10 Uncertain:1

Jan 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with autosomal recessive infantile type I muscle fibre disease and cardiomyopathy (PMID: 23365102). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Pro144Leufs*3) in the MYL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the MYL2 protein. ClinVar contains an entry for this variant (Variation ID: 191580). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Hypertrophic cardiomyopathy Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.431delC variant, located in coding exon 7 of the MYL2 gene, results from a deletion of one nucleotide at position 431, causing a translational frameshift with a predicted alternate stop codon (p.P144Lfs*3). This alteration occurs at the 3' terminus of theMYL2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration was reported in two siblings with infantile type I muscle fibre disease and cardiomyopathy, both with c.432delT in trans. The parents were each heterozygous for only one of the two alterations and did not show indications of cardiomyopathy (Weterman MA et al. Brain, 2013 Jan;136:282-93). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs786205430; hg19: chr12-111348950;