4-119136554-A-C

Position:

chr4-119136554-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016599.5(MYOZ2):c.29A>C(p.Gln10Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,613,748 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q10R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 28 hom. )

Consequence

MYOZ2
NM_016599.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 6.79

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]

MYOZ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008525193).

BP6

Variant 4-119136554-A-C is Benign according to our data. Variant chr4-119136554-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 45780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-119136554-A-C is described in Lovd as [Benign]. Variant chr4-119136554-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00125 (190/152366) while in subpopulation EAS AF= 0.0338 (175/5184). AF 95% confidence interval is 0.0297. There are 6 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOZ2	NM_016599.5 linkuse as main transcript	c.29A>C	p.Gln10Pro	missense_variant	2/6	ENST00000307128.6
MYOZ2	XM_006714234.5 linkuse as main transcript	c.29A>C	p.Gln10Pro	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOZ2	ENST00000307128.6 linkuse as main transcript	c.29A>C	p.Gln10Pro	missense_variant	2/6	1	NM_016599.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0335

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00264

AC:

662

AN:

250898

Hom.:

AF XY:

0.00265

AC XY:

359

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0328

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00105

AC:

1540

AN:

1461382

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

793

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0332

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152366

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0338

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00173

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00266

AC:

323

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 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	Nov 20, 2012	Gln10Pro in exon 2 of MYOZ2: This variant is not expected to have clinical signi ficance because it has been identified in 4.2% (24/572) of Asian chromosomes fro m a broad population by the 1000 Genomes project (dbSNP rs76757102). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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.29A>C (p.Gln10Pro) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 320/118584 control chromosomes (5 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.033583 (287/8546). This frequency is about 1343 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 East Asian origin. In addition, multiple clinical diagnostic laboratories in ClinVar have classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature, nor has it been functionally characterized. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy 16

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 07, 2018

- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 31, 2019

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2016

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

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.80

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

REVEL

Benign

0.23

Sift

Uncertain

0.011

Sift4G

Uncertain

0.022

Polyphen

0.82

Vest4

0.62

MVP

0.86

MPC

0.53

ClinPred

0.042

GERP RS

5.7

Varity_R

0.70

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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