12-110911082-CCTTCT-C

Position:

• chr12-110911082-CCTTCT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000432.4(MYL2):​c.491_495delAGAAG​(p.Glu164fs) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.63

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 6 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. Fraction of 0.02 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110911082-CCTTCT-C is Pathogenic according to our data. Variant chr12-110911082-CCTTCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 626788.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.491_495delAGAAG	p.Glu164fs	frameshift_variant	7/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.449_453delAGAAG	p.Glu150fs	frameshift_variant	6/6		NP_001393674.1
MYL2	NM_001406916.1	c.434_438delAGAAG	p.Glu145fs	frameshift_variant	7/7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.491_495delAGAAG	p.Glu164fs	frameshift_variant	7/7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.449_453delAGAAG	p.Glu150fs	frameshift_variant	6/6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.434_438delAGAAG	p.Glu145fs	frameshift_variant	7/7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 07, 2020

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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: rs1592798444; hg19: chr12-111348886;