12-110913096-C-T

Variant names:

• chr12-110913096-C-T
• rs727504408
• NM_000432.4:c.402G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000432.4(MYL2):​c.402G>A​(p.Glu134Glu) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.402G>A	p.Glu134Glu	splice_region_variant, synonymous_variant	Exon 6 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.360G>A	p.Glu120Glu	splice_region_variant, synonymous_variant	Exon 5 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.345G>A	p.Glu115Glu	splice_region_variant, synonymous_variant	Exon 6 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.402G>A	p.Glu134Glu	splice_region_variant, synonymous_variant	Exon 6 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.360G>A	p.Glu120Glu	splice_region_variant, synonymous_variant	Exon 5 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.345G>A	p.Glu115Glu	splice_region_variant, synonymous_variant	Exon 6 of 7			ENSP00000499568.1
MYL2	ENST00000549029.1	n.*37G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504408; hg19: chr12-111350900; COSMIC: COSV57406204; COSMIC: COSV57406204;