rs28711516

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002471.4(MYH6):c.166G>A(p.Gly56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0774 in 1,614,154 control chromosomes in the GnomAD database, including 5,295 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. G56G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.069 ( 398 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4897 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.70

Publications

27 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):

MYH-6 related congenital heart defects
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 14
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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: NO_KNOWN Submitted by: ClinGen

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030651689).

BP6

Variant 14-23407058-C-T is Benign according to our data. Variant chr14-23407058-C-T is described in ClinVar as Benign. ClinVar VariationId is 44455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0828 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.166G>A	p.Gly56Arg	missense	Exon 3 of 39	NP_002462.2	P13533

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH6	ENST00000405093.9	TSL:5 MANE Select	c.166G>A	p.Gly56Arg	missense	Exon 3 of 39	ENSP00000386041.3	P13533
MYH6	ENST00000968262.1		c.166G>A	p.Gly56Arg	missense	Exon 3 of 39	ENSP00000638321.1
MYH6	ENST00000968257.1		c.166G>A	p.Gly56Arg	missense	Exon 3 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes

AF:

0.0695

AC:

10577

AN:

152192

Hom.:

397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0591

Gnomad AMI

AF:

0.0617

Gnomad AMR

AF:

0.0508

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.0140

Gnomad SAS

AF:

0.0779

Gnomad FIN

AF:

0.0500

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0847

Gnomad OTH

AF:

0.0810

GnomAD2 exomes

AF:

0.0683

AC:

17171

AN:

251470

AF XY:

0.0717

show subpopulations

Gnomad AFR exome

AF:

0.0559

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.0131

Gnomad FIN exome

AF:

0.0459

Gnomad NFE exome

AF:

0.0835

Gnomad OTH exome

AF:

0.0764

GnomAD4 exome

AF:

0.0783

AC:

114408

AN:

1461844

Hom.:

4897

Cov.:

AF XY:

0.0790

AC XY:

57449

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0604

AC:

2022

AN:

33478

American (AMR)

AF:

0.0429

AC:

1917

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

2932

AN:

26136

East Asian (EAS)

AF:

0.00957

AC:

380

AN:

39700

South Asian (SAS)

AF:

0.0814

AC:

7024

AN:

86246

European-Finnish (FIN)

AF:

0.0490

AC:

2619

AN:

53412

Middle Eastern (MID)

AF:

0.0936

AC:

540

AN:

5768

European-Non Finnish (NFE)

AF:

0.0829

AC:

92134

AN:

1111986

Other (OTH)

AF:

0.0801

AC:

4840

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

6546

13093

19639

26186

32732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3322

6644

9966

13288

16610

<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:

0.0694

AC:

10576

AN:

152310

Hom.:

398

Cov.:

AF XY:

0.0668

AC XY:

4976

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0590

AC:

2453

AN:

41566

American (AMR)

AF:

0.0506

AC:

774

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

361

AN:

3468

East Asian (EAS)

AF:

0.0139

AC:

AN:

5188

South Asian (SAS)

AF:

0.0780

AC:

376

AN:

4822

European-Finnish (FIN)

AF:

0.0500

AC:

531

AN:

10624

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0847

AC:

5760

AN:

68024

Other (OTH)

AF:

0.0806

AC:

170

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

518

1036

1555

2073

2591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0807

Hom.:

1649

Bravo

AF:

0.0691

TwinsUK

AF:

0.0839

AC:

311

ALSPAC

AF:

0.0802

AC:

309

ESP6500AA

AF:

0.0645

AC:

284

ESP6500EA

AF:

0.0883

AC:

759

ExAC

AF:

0.0698

AC:

8472

Asia WGS

AF:

0.0430

AC:

148

AN:

3476

EpiCase

AF:

0.0925

EpiControl

AF:

0.0900

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (5)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.9

PhyloP100

2.7

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.97

Vest4

0.17

MutPred

0.59

Gain of solvent accessibility (P = 0.0037)

MPC

1.2

ClinPred

0.047

GERP RS

3.5

Varity_R

0.40

gMVP

0.76

Mutation Taster

=97/3

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

Computational scores

Splicing

Publications

Other links and lift over