rs104894368

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The ENST00000228841.15(MYL2):c.64G>T(p.Glu22Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYL2
ENST00000228841.15 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.53

Variant links:

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]

MYL2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 51 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYL2	NM_000432.4 linkuse as main transcript	c.64G>T	p.Glu22Ter	stop_gained	2/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1 linkuse as main transcript	c.64G>T	p.Glu22Ter	stop_gained	2/6		NP_001393674.1
MYL2	NM_001406916.1 linkuse as main transcript	c.7G>T	p.Glu3Ter	stop_gained	2/7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYL2	ENST00000228841.15 linkuse as main transcript	c.64G>T	p.Glu22Ter	stop_gained	2/7	1	NM_000432.4	ENSP00000228841	P1
MYL2	ENST00000548438.1 linkuse as main transcript	c.64G>T	p.Glu22Ter	stop_gained	2/6	3		ENSP00000447154
MYL2	ENST00000663220.1 linkuse as main transcript	c.7G>T	p.Glu3Ter	stop_gained	2/7			ENSP00000499568
MYL2	ENST00000546404.1 linkuse as main transcript	c.64G>T	p.Glu22Ter	stop_gained	2/2	2		ENSP00000499645

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251472

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727142

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2014

p.Glu22Stop (GAA>TAA): c.64 G>T in exon 2 of the MYL2 gene (NM_000432.3). The Glu22Stop mutation in the MYL2 gene has been reported in one individual who was part of the Framingham and Jackson Heart Study cohort (Bick et al., 2012). This individual had left ventricular wall thickness that measured within in the normal range (Bick et al., 2012). Glu22 stop may cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, no other nonsense mutations in the MYL2 gene have been reported in association with HCM. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

The p.E22* variant (also known as c.64G>T), located in coding exon 2 of the MYL2 gene, results from a G to T substitution at nucleotide position 64. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. The predicted stop codon occurs in the 5’ end of theMYL2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant has been reported in one participant from the Jackson Heart Study cohort, whose echocardiogram values were not indicative of cardiac disease at the time of evaluation (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.97

MutationTaster

Benign

1.0

A;A

Vest4

0.83

GERP RS

4.4

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over