4-119136516-CA-CAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_016599.5(MYOZ2):c.-3dupA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,438 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 6 hom. )

Consequence

MYOZ2
NM_016599.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.31

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy 16
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYOZ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 4-119136516-C-CA is Benign according to our data. Variant chr4-119136516-C-CA is described in ClinVar as Benign. ClinVar VariationId is 45778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00534 (812/152014) while in subpopulation AFR AF = 0.0169 (699/41464). AF 95% confidence interval is 0.0158. There are 6 homozygotes in GnomAd4. There are 385 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 812 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
MYOZ2	NM_016599.5 link	c.-3dupA	5_prime_UTR_variant	Exon 2 of 6	ENST00000307128.6	NP_057683.1
MYOZ2	NM_001440645.1 link	c.-3dupA	5_prime_UTR_variant	Exon 2 of 7		NP_001427574.1
MYOZ2	NM_001440646.1 link	c.-3dupA	5_prime_UTR_variant	Exon 2 of 6		NP_001427575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOZ2	ENST00000307128.6 link	c.-3dupA		5_prime_UTR_variant	Exon 2 of 6	1	NM_016599.5	ENSP00000306997.6

Frequencies

GnomAD3 genomes

AF:

0.00530

AC:

805

AN:

151896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00629

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00116

AC:

290

AN:

249782

AF XY:

0.000859

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.000900

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.000559

AC:

817

AN:

1460424

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

342

AN XY:

726522

show subpopulations

African (AFR)

AF:

0.0192

AC:

641

AN:

33410

American (AMR)

AF:

0.00128

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1110972

Other (OTH)

AF:

0.00167

AC:

101

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00534

AC:

812

AN:

152014

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

385

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0169

AC:

699

AN:

41464

American (AMR)

AF:

0.00628

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67948

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00677

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was found in CARDIOMYOPATHY,CRDMV2-PANCARD -

Feb 25, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

-3_-2insA in exon 2 of MYOZ2: This variant is not expected to have clinical sign ificance because it has been identified in 1.2% (51/4268) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/) . -3_-2insA in exon 2 of MYOZ2 (allele frequency = 1.2%, 51/4268) ** -

Cardiomyopathy

Benign:1

May 03, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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.-3dupA variant (also known as c.-3_-2insA) involves insertion of a nucleotide in non-coding exon 2. Mutation taster predicts a benign 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 176/115548 control chromosomes (1 homozygote) from ExAC, predominantly observed in the African subpopulation at a frequency of 0.015706 (157/9996). This frequency is about 628 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 African 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. -

Cardiovascular phenotype

Benign:1

Feb 13, 2018

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. -

Hypertrophic cardiomyopathy 16

Benign:1

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over