12-110913289-T-G

Position:

• chr12-110913289-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000432.4(MYL2):​c.310A>C​(p.Lys104Gln) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K104E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 7 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 chr12-110913289-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.310A>C	p.Lys104Gln	missense_variant	5/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.268A>C	p.Lys90Gln	missense_variant	4/6		NP_001393674.1
MYL2	NM_001406916.1	c.253A>C	p.Lys85Gln	missense_variant	5/7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.310A>C	p.Lys104Gln	missense_variant	5/7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.268A>C	p.Lys90Gln	missense_variant	4/6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.253A>C	p.Lys85Gln	missense_variant	5/7			ENSP00000499568.1
MYL2	ENST00000549029.1	n.141A>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 05, 2019

This missense variant replaces lysine with glutamine at codon 104 of the MYL2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.064	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.90	P;.
Vest4		0.83
MutPred		0.54		Loss of methylation at K104 (P = 0.0042);.;
MVP		0.89
MPC		0.71
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.55
gMVP		0.79

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: rs199474811; hg19: chr12-111351093;