rs397516406

Positions:

• chr12-110911093-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000432.4(MYL2):​c.485G>A​(p.Gly162Glu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G162R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-110911094-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132976.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, not_provided=1, Likely_pathogenic=3}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 12-110911093-C-T is Pathogenic according to our data. Variant chr12-110911093-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110911093-C-T is described in Lovd as [Pathogenic]. Variant chr12-110911093-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.485G>A	p.Gly162Glu	missense_variant	7/7	ENST00000228841.15
MYL2	NM_001406745.1	c.443G>A	p.Gly148Glu	missense_variant	6/6
MYL2	NM_001406916.1	c.428G>A	p.Gly143Glu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.485G>A	p.Gly162Glu	missense_variant	7/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.443G>A	p.Gly148Glu	missense_variant	6/6	3
MYL2	ENST00000663220.1	c.428G>A	p.Gly143Glu	missense_variant	7/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 19, 2023

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 06, 2021

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.54		Loss of ubiquitination at K165 (P = 0.0605);.;
MVP		0.94
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516406; hg19: chr12-111348897;