rs727503297

Positions:

• chr12-110913324-C-A
• chr12-110913324-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000432.4(MYL2):​c.275G>T​(p.Gly92Val) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. 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. G92E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57

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 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.275G>T	p.Gly92Val	missense_variant, splice_region_variant	5/7	ENST00000228841.15
MYL2	NM_001406745.1	c.233G>T	p.Gly78Val	missense_variant, splice_region_variant	4/6
MYL2	NM_001406916.1	c.218G>T	p.Gly73Val	missense_variant, splice_region_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.275G>T	p.Gly92Val	missense_variant, splice_region_variant	5/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.233G>T	p.Gly78Val	missense_variant, splice_region_variant	4/6	3
MYL2	ENST00000663220.1	c.218G>T	p.Gly73Val	missense_variant, splice_region_variant	5/7
MYL2	ENST00000549029.1	n.106G>T		splice_region_variant, 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 23, 2018

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly92Val variant in MYL2 has been identified by our laboratory in 1 neonate with HCM and segregated with disease in 4 affected relatives. It was absent from large popula tion studies. Computational prediction tools and conservation analysis suggest t hat this variant may impact the protein. In addition, this variant is located in the first base of the exon, which is part of the 3? splice region and splicing computational tools predict a splicing impact. However, predictions from computa tional tools are not predictive enough to determine pathogenicity. In summary, w hile there is some suspicion for a pathogenic role, the clinical significance of the p.Gly92Val variant is uncertain. ACMG/AMP Criteria applied: PM2, PP1, PP3. -

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 164476). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 92 of the MYL2 protein (p.Gly92Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Uncertain	0.74
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.3	D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.52		Loss of ubiquitination at K91 (P = 0.0391);.;
MVP		0.93
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503297; hg19: chr12-111351128;