12-110914267-C-T

Variant names:

• chr12-110914267-C-T
• rs397516398
• NM_000432.4:c.193G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000432.4(MYL2):​c.193G>A​(p.Glu65Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 7.50
• Publications: 1 publications found

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]

MYL2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39564 (below the threshold of 3.09). Trascript score misZ: 1.1124 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 10, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, congenital fiber-type disproportion myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000432.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	NM_000432.4	MANE Select	c.193G>A	p.Glu65Lys	missense	Exon 4 of 7	NP_000423.2	P10916
	MYL2	NM_001406745.1		c.151G>A	p.Glu51Lys	missense	Exon 3 of 6	NP_001393674.1	G3V1V8
	MYL2	NM_001406916.1		c.136G>A	p.Glu46Lys	missense	Exon 4 of 7	NP_001393845.1	A0A590UJU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	ENST00000228841.15	TSL:1 MANE Select	c.193G>A	p.Glu65Lys	missense	Exon 4 of 7	ENSP00000228841.8	P10916
	MYL2	ENST00000713800.1		c.193G>A	p.Glu65Lys	missense	Exon 5 of 8	ENSP00000519106.1	P10916
	MYL2	ENST00000713803.1		c.193G>A	p.Glu65Lys	missense	Exon 5 of 8	ENSP00000519109.1	P10916

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hypertrophic cardiomyopathy 10 (2)
-	2	-	not provided (2)
1	-	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.70
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.81
MutPred		0.50		Gain of ubiquitination at E65 (P = 0.0238)
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.73
gMVP		0.95
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397516398; hg19: chr12-111352071;