NM_002471.4:c.3369G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM2BP4_StrongBP6_Very_StrongBP7BS2

The NM_002471.4(MYH6):c.3369G>A(p.Glu1123Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.138

Publications

0 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 -15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 14-23390420-C-T is Benign according to our data. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390420-C-T is described in CliVar as Likely_benign. Clinvar id is 227588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.138 with no splicing effect.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.3369G>A	p.Glu1123Glu	synonymous_variant	Exon 26 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.3369G>A	p.Glu1123Glu	synonymous_variant	Exon 26 of 39	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460050

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111794

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu1123Glu in exon 26 of MYH6: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. -

Cardiovascular phenotype

Benign:1

Jan 17, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.6

(source)

DANN

Benign

0.74

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over