rs192057022

chr12-110913139-C-Achr12-110913139-C-T

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.359G>T(p.Arg120Leu) variant causes a missense change involving the alteration of a non-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. R120Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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 53 pathogenic changes around while only 9 benign (85%) 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 chr12-110913140-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.359G>T	p.Arg120Leu	missense_variant	6/7	ENST00000228841.15
MYL2	NM_001406745.1	c.317G>T	p.Arg106Leu	missense_variant	5/6
MYL2	NM_001406916.1	c.302G>T	p.Arg101Leu	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.359G>T	p.Arg120Leu	missense_variant	6/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.317G>T	p.Arg106Leu	missense_variant	5/6	3
MYL2	ENST00000663220.1	c.302G>T	p.Arg101Leu	missense_variant	6/7
MYL2	ENST00000549029.1	n.291G>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
CardioboostCm	Benign	0.048
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.030	D;T
Polyphen		0.31	B;.
Vest4		0.50
MutPred		0.59		Gain of catalytic residue at K115 (P = 0.007);.;
MVP		0.87
MPC		0.69
ClinPred		0.82	D
GERP RS		-0.34
Varity_R		0.19
gMVP		0.67

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: rs192057022; hg19: chr12-111350943; COSMIC: COSV57406866;