rs587782965

Variant names:

• chr12-110914221-G-T
• rs587782965
• NM_000432.4:c.239C>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000432.4(MYL2):​c.239C>A​(p.Thr80Asn) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T80T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.51
• Publications: 2 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: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 15 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, 24 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, 0.88
• PP5: Variant 12-110914221-G-T is Pathogenic according to our data. Variant chr12-110914221-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 155818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	NM_000432.4	MANE Select	c.239C>A	p.Thr80Asn	missense	Exon 4 of 7	NP_000423.2
	MYL2	NM_001406745.1		c.197C>A	p.Thr66Asn	missense	Exon 3 of 6	NP_001393674.1
	MYL2	NM_001406916.1		c.182C>A	p.Thr61Asn	missense	Exon 4 of 7	NP_001393845.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	ENST00000228841.15	TSL:1 MANE Select	c.239C>A	p.Thr80Asn	missense	Exon 4 of 7	ENSP00000228841.8
	MYL2	ENST00000713800.1		c.239C>A	p.Thr80Asn	missense	Exon 5 of 8	ENSP00000519106.1
	MYL2	ENST00000713803.1		c.239C>A	p.Thr80Asn	missense	Exon 5 of 8	ENSP00000519109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Hypertrophic cardiomyopathy 10 (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.49		Gain of catalytic residue at T80 (P = 0)
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.79
gMVP		0.83
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782965; hg19: chr12-111352025;