rs140126678

chr4-119186143-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_016599.5(MYOZ2):c.738A>G(p.Ile246Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,614,050 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. I246T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 14 hom. )

Consequence

MYOZ2
NM_016599.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6O:1

Conservation

PhyloP100: -0.00800

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028900564).

BP6

Variant 4-119186143-A-G is Benign according to our data. Variant chr4-119186143-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 30509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-119186143-A-G is described in Lovd as [Likely_benign]. Variant chr4-119186143-A-G is described in Lovd as [Likely_pathogenic]. Variant chr4-119186143-A-G is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd at 307 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOZ2	NM_016599.5 linkuse as main transcript	c.738A>G	p.Ile246Met	missense_variant	6/6	ENST00000307128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOZ2	ENST00000307128.6 linkuse as main transcript	c.738A>G	p.Ile246Met	missense_variant	6/6	1	NM_016599.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00214

AC:

538

AN:

251240

Hom.:

AF XY:

0.00209

AC XY:

284

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0216

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000987

AC:

1443

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000948

AC XY:

689

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0214

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.00202

AC:

307

AN:

152308

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

236

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0245

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000938

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00189

AC:

230

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYOZ2)	Apr 20, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	MYOZ2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2021	This variant is associated with the following publications: (PMID: 22987565, 23299917, 17347475) -

Hypertrophic cardiomyopathy 16

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2012

Ile246Met in exon 6 of MYOZ2: This variant is not expected to have clinical sign ificance because it has been identified in 2.1% (4/186) of Finnish chromosomes ( 1000 Genomes Project, dbSNP rs140126678). In addition, the affected amino acid is poorly conserved in evolution, also suggesting that a change at this position is tolerated. Ile246Met in exon 6 of MYOZ2 (rs140126678; allele frequency = 2. 1%, 4/186) -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.17

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.14

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.81

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.062

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.12

REVEL

Benign

0.28

Sift

Uncertain

0.011

Sift4G

Benign

0.29

Polyphen

0.041

Vest4

0.64

MVP

0.54

MPC

0.17

ClinPred

0.027

GERP RS

-1.7

Varity_R

0.092

gMVP

0.34

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

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