NM_002471.4:c.999C>T

Variant names:

Variant summary

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

The NM_002471.4(MYH6):c.999C>T(p.Thr333Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,290 control chromosomes in the GnomAD database, including 497 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. T333T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 223 hom., cov: 30)

Exomes 𝑓: 0.011 ( 274 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -7.33

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 14-23402700-G-A is Benign according to our data. Variant chr14-23402700-G-A is described in ClinVar as Benign. ClinVar VariationId is 36634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.999C>T	p.Thr333Thr	synonymous_variant	Exon 11 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 link	c.999C>T	p.Thr333Thr	synonymous_variant	Exon 11 of 39	5	NM_002471.4	ENSP00000386041.3
MYH6	ENST00000557461.2 link	n.1066C>T		non_coding_transcript_exon_variant	Exon 11 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

5213

AN:

151346

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0263

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.000596

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.0224

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.0409

GnomAD2 exomes

AF:

0.0183

AC:

4597

AN:

251260

AF XY:

0.0175

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0290

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.00929

Gnomad OTH exome

AF:

0.0217

GnomAD4 exome

AF:

0.0110

AC:

16064

AN:

1461826

Hom.:

274

Cov.:

AF XY:

0.0114

AC XY:

8303

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0936

AC:

3133

AN:

33478

American (AMR)

AF:

0.0199

AC:

888

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

676

AN:

26134

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0264

AC:

2279

AN:

86258

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.0524

AC:

302

AN:

5768

European-Non Finnish (NFE)

AF:

0.00683

AC:

7595

AN:

1111996

Other (OTH)

AF:

0.0192

AC:

1161

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1019

2038

3058

4077

5096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.0345

AC:

5227

AN:

151464

Hom.:

223

Cov.:

AF XY:

0.0334

AC XY:

2469

AN XY:

74002

show subpopulations

African (AFR)

AF:

0.0976

AC:

4026

AN:

41238

American (AMR)

AF:

0.0262

AC:

399

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3464

East Asian (EAS)

AF:

0.000598

AC:

AN:

5018

South Asian (SAS)

AF:

0.0238

AC:

114

AN:

4780

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.0241

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00744

AC:

505

AN:

67894

Other (OTH)

AF:

0.0438

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

215

430

645

860

1075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0174

Hom.:

Bravo

AF:

0.0377

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

Sep 29, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 25, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

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

Cardiomyopathy

Benign:1

Nov 20, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Cardiovascular phenotype

Benign:1

Jun 26, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.9

(source)

DANN

Benign

0.94

PhyloP100

-7.3

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