4-119151032-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 0.221
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
MYOZ2NM_016599.5 linkc.237A>G p.Ala79Ala synonymous_variant Exon 3 of 6 ENST00000307128.6 NP_057683.1 Q9NPC6
MYOZ2XM_006714234.5 linkc.237A>G p.Ala79Ala synonymous_variant Exon 3 of 6 XP_006714297.1
LOC105379404XR_001741421.2 linkn.-73T>C upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYOZ2ENST00000307128.6 linkc.237A>G p.Ala79Ala synonymous_variant Exon 3 of 6 1 NM_016599.5 ENSP00000306997.6 Q9NPC6

Frequencies

GnomAD3 genomes
AF:
0.00931
AC:
1417
AN:
152216
Hom.:
5
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Sep 08, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 20, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 16 Benign:4
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 10, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3Other:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MYOZ2: BP4, BP7, BS1, BS2 -

Apr 20, 2012
Leiden Muscular Dystrophy (MYOZ2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Aug 25, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 10, 2016
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1
Jan 31, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Nov 13, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

MYOZ2-related disorder Benign:1
Jul 15, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

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

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

Other links and lift over

dbSNP: rs17851524; hg19: chr4-120072187; API