12-110911146-AG-AGG

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000432.4(MYL2):​c.431dupC​(p.Asp145fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,018 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYL2 NM_000432.4 frameshift
• Clinical Significance: Not reported in ClinVar
• 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 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. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.431dupC	p.Asp145fs	frameshift_variant	Exon 7 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.389dupC	p.Asp131fs	frameshift_variant	Exon 6 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.374dupC	p.Asp126fs	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.431dupC	p.Asp145fs	frameshift_variant	Exon 7 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.389dupC	p.Asp131fs	frameshift_variant	Exon 6 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.374dupC	p.Asp126fs	frameshift_variant	Exon 7 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398018 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694346

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: 0.0000207

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111348950;