rs17851524

Positions:

• chr4-119151032-A-G
• chr4-119151032-A-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016599.5(MYOZ2):​c.237A>G​(p.Ala79Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,610,914 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (5 hom., cov: 32)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: MYOZ2 NM_016599.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 0.221

Genes affected

MYOZ2 (HGNC:1330): (myozenin 2) The protein encoded by this gene belongs to a family of sarcomeric proteins that bind to calcineurin, a phosphatase involved in calcium-dependent signal transduction in diverse cell types. These family members tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells, and thus they are important for calcineurin signaling. Mutations in this gene cause cardiomyopathy familial hypertrophic type 16, a hereditary heart disorder. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-119151032-A-G is Benign according to our data. Variant chr4-119151032-A-G is described in ClinVar as [Benign]. Clinvar id is 31788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-119151032-A-G is described in Lovd as [Benign]. Variant chr4-119151032-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.221 with no splicing effect.
• BS2: High AC in GnomAd4 at 1416 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOZ2	NM_016599.5	c.237A>G	p.Ala79Ala	synonymous_variant	3/6	ENST00000307128.6	NP_057683.1
MYOZ2	XM_006714234.5	c.237A>G	p.Ala79Ala	synonymous_variant	3/6		XP_006714297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOZ2	ENST00000307128.6	c.237A>G	p.Ala79Ala	synonymous_variant	3/6	1	NM_016599.5	ENSP00000306997.6

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1417 AN: 152216 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00947 AC: 2377 AN: 251068 Hom.: 19 AF XY: 0.00997 AC XY: 1353 AN XY: 135718

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0124 AC: 18126 AN: 1458580 Hom.: 143 Cov.: 33 AF XY: 0.0121 AC XY: 8817 AN XY: 725858

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00785

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.00617

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00930 AC: 1416 AN: 152334 Hom.: 5 Cov.: 32 AF XY: 0.00861 AC XY: 641 AN XY: 74488

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0117 Hom.: 8

Bravo AF: 0.00945

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0168

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 08, 2011	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 16 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYOZ2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYOZ2)	Apr 20, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2017	Variant summary: The MYOZ2 c.237A>G (p.Ala79Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may not affect binding of ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1202/121194 control chromosomes (9 homozygotes) from ExAC, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.014932 (995/66636). This frequency is about 597 times the estimated maximal expected allele frequency of a pathogenic MYOZ2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories in ClinVar have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature. Taken together, this variant is classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 10, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

MYOZ2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.7
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17851524; hg19: chr4-120072187;