rs7687613

Positions:

• chr4-119164293-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016599.5(MYOZ2):​c.459A>G​(p.Glu153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.036 in 1,613,936 control chromosomes in the GnomAD database, including 2,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (728 hom., cov: 31)
  • Exomes 𝑓: 0.033 (1280 hom.)
• Consequence: MYOZ2 NM_016599.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.68

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 4-119164293-A-G is Benign according to our data. Variant chr4-119164293-A-G is described in ClinVar as [Benign]. Clinvar id is 31786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-119164293-A-G is described in Lovd as [Benign]. Variant chr4-119164293-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOZ2	NM_016599.5	c.459A>G	p.Glu153=	synonymous_variant	5/6	ENST00000307128.6
MYOZ2	XM_006714234.5	c.459A>G	p.Glu153=	synonymous_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOZ2	ENST00000307128.6	c.459A>G	p.Glu153=	synonymous_variant	5/6	1	NM_016599.5	P1

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10619 AN: 152178 Hom.: 731 Cov.: 31

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0361

Gnomad EAS AF: 0.0358

Gnomad SAS AF: 0.0577

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0592

GnomAD3 exomes AF: 0.0424 AC: 10649 AN: 251304 Hom.: 432 AF XY: 0.0406 AC XY: 5516 AN XY: 135826

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0361

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.0359

Gnomad SAS exome AF: 0.0611

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0398

GnomAD4 exome AF: 0.0325 AC: 47555 AN: 1461640 Hom.: 1280 Cov.: 31 AF XY: 0.0334 AC XY: 24271 AN XY: 727128

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.0317

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.0626

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0418

GnomAD4 genome AF: 0.0697 AC: 10621 AN: 152296 Hom.: 728 Cov.: 31 AF XY: 0.0691 AC XY: 5144 AN XY: 74482

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0440

Gnomad4 ASJ AF: 0.0361

Gnomad4 EAS AF: 0.0355

Gnomad4 SAS AF: 0.0572

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0600

Alfa AF: 0.0382 Hom.: 317

Bravo AF: 0.0755

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0294

EpiControl AF: 0.0283

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 22, 2011	- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 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. -

Hypertrophic cardiomyopathy 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Sep 21, 2015

- -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (MYOZ2)

Apr 20, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.8
DANN	Benign	0.55

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: rs7687613; hg19: chr4-120085448; COSMIC: COSV61085644;