14-23389062-AGGG-AGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_002471.4(MYH6):c.3979-8delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.35 ( 8254 hom., cov: 0)

Exomes 𝑓: 0.31 ( 26611 hom. )

Failed GnomAD Quality Control

Consequence

MYH6
NM_002471.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9O:2

Conservation

PhyloP100: 0.275

Publications

5 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 -9 ACMG points.

BP6

Variant 14-23389062-AG-A is Benign according to our data. Variant chr14-23389062-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36628.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.3979-8delC		splice_region_variant, intron_variant	Intron 28 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 link	c.3979-8delC		splice_region_variant, intron_variant	Intron 28 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

40782

AN:

115534

Hom.:

8236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.612

Gnomad AMI

AF:

0.318

Gnomad AMR

AF:

0.236

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.317

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.260

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.338

GnomAD2 exomes

AF:

0.320

AC:

44689

AN:

139674

AF XY:

0.320

show subpopulations

Gnomad AFR exome

AF:

0.610

Gnomad AMR exome

AF:

0.262

Gnomad ASJ exome

AF:

0.283

Gnomad EAS exome

AF:

0.271

Gnomad FIN exome

AF:

0.283

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.308

AC:

297903

AN:

966060

Hom.:

26611

Cov.:

AF XY:

0.307

AC XY:

147489

AN XY:

479754

show subpopulations

African (AFR)

AF:

0.616

AC:

18501

AN:

30024

American (AMR)

AF:

0.250

AC:

6265

AN:

25092

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

4699

AN:

17628

East Asian (EAS)

AF:

0.260

AC:

5114

AN:

19658

South Asian (SAS)

AF:

0.350

AC:

21151

AN:

60378

European-Finnish (FIN)

AF:

0.254

AC:

7748

AN:

30466

Middle Eastern (MID)

AF:

0.314

AC:

1225

AN:

3902

European-Non Finnish (NFE)

AF:

0.298

AC:

219961

AN:

737912

Other (OTH)

AF:

0.323

AC:

13239

AN:

41000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6230

12460

18691

24921

31151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8586

17172

25758

34344

42930

<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:

0.353

AC:

40854

AN:

115646

Hom.:

8254

Cov.:

AF XY:

0.345

AC XY:

19621

AN XY:

56834

show subpopulations

African (AFR)

AF:

0.612

AC:

23773

AN:

38846

American (AMR)

AF:

0.236

AC:

2658

AN:

11280

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

609

AN:

2598

East Asian (EAS)

AF:

0.157

AC:

477

AN:

3032

South Asian (SAS)

AF:

0.317

AC:

1085

AN:

3426

European-Finnish (FIN)

AF:

0.179

AC:

1265

AN:

7078

Middle Eastern (MID)

AF:

0.264

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.217

AC:

10173

AN:

46880

Other (OTH)

AF:

0.337

AC:

535

AN:

1588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

1127

2254

3380

4507

5634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 09, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

Aug 08, 2017

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiomyopathy

Benign:2

Apr 04, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 18, 2011

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Dilated Cardiomyopathy, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Atrial septal defect

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy 14

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Sep 30, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

Hypertrophic cardiomyopathy 2

Other:1

Institute of Human Genetics, University of Wuerzburg

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.28

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over