12-110919145-A-T

Variant names:

• chr12-110919145-A-T
• NM_000432.4:c.52T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000432.4(MYL2):​c.52T>A​(p.Phe18Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F18L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.90

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 8 ACMG points.

• PM1: In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) 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 chr12-110919145-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.52T>A	p.Phe18Ile	missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.52T>A	p.Phe18Ile	missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.-6T>A		5_prime_UTR_variant	Exon 2 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.52T>A	p.Phe18Ile	missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.52T>A	p.Phe18Ile	missense_variant	Exon 2 of 6	3		ENSP00000447154.1
MYL2	ENST00000546404.1	c.52T>A	p.Phe18Ile	missense_variant	Exon 2 of 2	2		ENSP00000499645.1
MYL2	ENST00000663220.1	c.-6T>A		5_prime_UTR_variant	Exon 2 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Uncertain:1

Aug 31, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. Different missense changes at the same codon (p.Phe18Leu, p.Phe18Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014068, VCV000181425 /PMID: 9535554). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.57		Gain of catalytic residue at N16 (P = 0.0198);Gain of catalytic residue at N16 (P = 0.0198);
MVP		0.95
MPC		1.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111356949;