NM_002471.4:c.411G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002471.4(MYH6):c.411G>A(p.Glu137Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,614,008 control chromosomes in the GnomAD database, including 48,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3915 hom., cov: 32)

Exomes 𝑓: 0.24 ( 44921 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.342

Publications

19 publications found

Variant links:

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy 14
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
Keppen-Lubinsky syndrome
Inheritance: AD Classification: MODERATE Submitted by: Illumina
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
atrial septal defect 3
Inheritance: AD Classification: LIMITED Submitted by: G2P
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 14-23405314-C-T is Benign according to our data. Variant chr14-23405314-C-T is described in ClinVar as Benign. ClinVar VariationId is 44504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.342 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.411G>A	p.Glu137Glu	synonymous	Exon 5 of 39	NP_002462.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.411G>A	p.Glu137Glu	synonymous	Exon 5 of 39	ENSP00000386041.3
	MYH6	ENST00000557461.2	TSL:5	n.478G>A		non_coding_transcript_exon	Exon 5 of 14

Frequencies

GnomAD3 genomes

AF:

0.218

AC:

33077

AN:

152074

Hom.:

3916

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.0561

Gnomad SAS

AF:

0.179

Gnomad FIN

AF:

0.210

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.261

Gnomad OTH

AF:

0.224

GnomAD2 exomes

AF:

0.207

AC:

52054

AN:

251464

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.0561

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.232

GnomAD4 exome

AF:

0.243

AC:

354887

AN:

1461816

Hom.:

44921

Cov.:

AF XY:

0.242

AC XY:

175697

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.167

AC:

5590

AN:

33474

American (AMR)

AF:

0.133

AC:

5949

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

7774

AN:

26136

East Asian (EAS)

AF:

0.0475

AC:

1887

AN:

39700

South Asian (SAS)

AF:

0.188

AC:

16210

AN:

86252

European-Finnish (FIN)

AF:

0.219

AC:

11694

AN:

53414

Middle Eastern (MID)

AF:

0.213

AC:

1229

AN:

5764

European-Non Finnish (NFE)

AF:

0.261

AC:

290331

AN:

1111970

Other (OTH)

AF:

0.236

AC:

14223

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

19985

39970

59956

79941

99926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9626

19252

28878

38504

48130

<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:

0.217

AC:

33090

AN:

152192

Hom.:

3915

Cov.:

AF XY:

0.215

AC XY:

15962

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.170

AC:

7054

AN:

41524

American (AMR)

AF:

0.194

AC:

2972

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1038

AN:

3472

East Asian (EAS)

AF:

0.0564

AC:

292

AN:

5178

South Asian (SAS)

AF:

0.179

AC:

861

AN:

4820

European-Finnish (FIN)

AF:

0.210

AC:

2225

AN:

10602

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.261

AC:

17764

AN:

67986

Other (OTH)

AF:

0.221

AC:

467

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1347

2694

4041

5388

6735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.243

Hom.:

7436

Bravo

AF:

0.211

Asia WGS

AF:

0.122

AC:

423

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.266

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

Sep 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy 14

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jun 16, 2015

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.0

(source)

DANN

Benign

0.55

PhyloP100

0.34

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over