rs727504300

Positions:

• chr12-110919150-TTG-TA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1 PM2 BP6

The NM_000432.4(MYL2):​c.45_46delinsT​(p.Asn16ThrfsTer34) variant causes a frameshift 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.76

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 Likely_pathogenic. Variant got 9 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 32 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-110919151-TG-A is Benign according to our data. Variant chr12-110919151-TG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177719.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.45_46delinsT	p.Asn16ThrfsTer34	frameshift_variant	2/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.45_46delinsT	p.Asn16ThrfsTer27	frameshift_variant	2/6		NP_001393674.1
MYL2	NM_001406916.1	c.-13_-12delinsT		5_prime_UTR_variant	2/7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.45_46delinsT	p.Asn16ThrfsTer34	frameshift_variant	2/7	1	NM_000432.4	ENSP00000228841	P1
MYL2	ENST00000546404.1	c.45_46delinsT	p.Asn16ThrfsTer61	frameshift_variant	2/2	2		ENSP00000499645
MYL2	ENST00000548438.1	c.45_46delinsT	p.Asn16ThrfsTer27	frameshift_variant	2/6	3		ENSP00000447154
MYL2	ENST00000663220.1	c.-13_-12delinsT		5_prime_UTR_variant	2/7			ENSP00000499568

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 08, 2016

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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504300; hg19: chr12-111356955;