NM_017534.6:c.399T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017534.6(MYH2):c.399T>A(p.Pro133Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,874 control chromosomes in the GnomAD database, including 156,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P133P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.42 ( 14035 hom., cov: 32)

Exomes 𝑓: 0.43 ( 142157 hom. )

Consequence

MYH2
NM_017534.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -5.26

Publications

17 publications found

Variant links:

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

MYH2 links:

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYHAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 17-10545452-A-T is Benign according to our data. Variant chr17-10545452-A-T is described in ClinVar as Benign. ClinVar VariationId is 260824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6 link	c.399T>A	p.Pro133Pro	synonymous_variant	Exon 5 of 40	ENST00000245503.10	NP_060004.3	Q9UKX2-1
MYH2	NM_001100112.2 link	c.399T>A	p.Pro133Pro	synonymous_variant	Exon 5 of 40		NP_001093582.1	Q9UKX2-1
MYHAS	NR_125367.1 link	n.168-22085A>T		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10 link	c.399T>A	p.Pro133Pro	synonymous_variant	Exon 5 of 40	1	NM_017534.6	ENSP00000245503.5		Q9UKX2-1

Frequencies

GnomAD3 genomes

AF:

0.416

AC:

63227

AN:

151904

Hom.:

14018

Cov.:

show subpopulations

Gnomad AFR

AF:

0.323

Gnomad AMI

AF:

0.454

Gnomad AMR

AF:

0.489

Gnomad ASJ

AF:

0.447

Gnomad EAS

AF:

0.833

Gnomad SAS

AF:

0.616

Gnomad FIN

AF:

0.451

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.403

Gnomad OTH

AF:

0.412

GnomAD2 exomes

AF:

0.487

AC:

122536

AN:

251398

AF XY:

0.487

show subpopulations

Gnomad AFR exome

AF:

0.320

Gnomad AMR exome

AF:

0.600

Gnomad ASJ exome

AF:

0.452

Gnomad EAS exome

AF:

0.849

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.403

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

AF:

0.430

AC:

629273

AN:

1461852

Hom.:

142157

Cov.:

AF XY:

0.435

AC XY:

316040

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.317

AC:

10600

AN:

33480

American (AMR)

AF:

0.584

AC:

26097

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.453

AC:

11829

AN:

26136

East Asian (EAS)

AF:

0.830

AC:

32963

AN:

39698

South Asian (SAS)

AF:

0.594

AC:

51251

AN:

86256

European-Finnish (FIN)

AF:

0.438

AC:

23383

AN:

53414

Middle Eastern (MID)

AF:

0.455

AC:

2625

AN:

5764

European-Non Finnish (NFE)

AF:

0.399

AC:

444095

AN:

1111986

Other (OTH)

AF:

0.438

AC:

26430

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

23787

47573

71360

95146

118933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14060

28120

42180

56240

70300

<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:

0.416

AC:

63288

AN:

152022

Hom.:

14035

Cov.:

AF XY:

0.428

AC XY:

31811

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.324

AC:

13440

AN:

41494

American (AMR)

AF:

0.489

AC:

7474

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.447

AC:

1551

AN:

3466

East Asian (EAS)

AF:

0.833

AC:

4300

AN:

5160

South Asian (SAS)

AF:

0.616

AC:

2960

AN:

4808

European-Finnish (FIN)

AF:

0.451

AC:

4767

AN:

10562

Middle Eastern (MID)

AF:

0.449

AC:

131

AN:

292

European-Non Finnish (NFE)

AF:

0.403

AC:

27385

AN:

67948

Other (OTH)

AF:

0.411

AC:

867

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1837

3674

5511

7348

9185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

612

1224

1836

2448

3060

<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:

0.371

Hom.:

3243

Bravo

AF:

0.413

Asia WGS

AF:

0.656

AC:

2275

AN:

3478

EpiCase

AF:

0.401

EpiControl

AF:

0.407

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 08, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myopathy, proximal, and ophthalmoplegia

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inclusion Body Myopathy, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.13

(source)

DANN

Benign

0.55

PhyloP100

-5.3

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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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