Genetic Variant MYH6:p.Arg143Arg (chr14-23405298-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002471.4(MYH6):c.427C>A(p.Arg143Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,614,114 control chromosomes in the GnomAD database, including 8,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 681 hom., cov: 32)

Exomes 𝑓: 0.10 ( 7691 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.496

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 14-23405298-G-T is Benign according to our data. Variant chr14-23405298-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 44507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23405298-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.496 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.427C>A	p.Arg143Arg	synonymous_variant	Exon 5 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.427C>A	p.Arg143Arg	synonymous_variant	Exon 5 of 39	5	NM_002471.4	ENSP00000386041.3		P13533
MYH6	ENST00000557461.2 link	n.494C>A		non_coding_transcript_exon_variant	Exon 5 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.0826

AC:

12563

AN:

152158

Hom.:

681

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.0560

Gnomad SAS

AF:

0.140

Gnomad FIN

AF:

0.0895

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0932

GnomAD3 exomes

AF:

0.0955

AC:

24013

AN:

251488

Hom.:

1363

AF XY:

0.101

AC XY:

13752

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.0706

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.0558

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.0920

Gnomad NFE exome

AF:

0.104

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.0996

AC:

145564

AN:

1461838

Hom.:

7691

Cov.:

AF XY:

0.102

AC XY:

73864

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.0734

Gnomad4 ASJ exome

AF:

0.124

Gnomad4 EAS exome

AF:

0.0474

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.0937

Gnomad4 NFE exome

AF:

0.101

Gnomad4 OTH exome

AF:

0.0983

GnomAD4 genome

AF:

0.0824

AC:

12553

AN:

152276

Hom.:

681

Cov.:

AF XY:

0.0826

AC XY:

6152

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0229

Gnomad4 AMR

AF:

0.108

Gnomad4 ASJ

AF:

0.126

Gnomad4 EAS

AF:

0.0563

Gnomad4 SAS

AF:

0.140

Gnomad4 FIN

AF:

0.0895

Gnomad4 NFE

AF:

0.104

Gnomad4 OTH

AF:

0.0918

Alfa

AF:

0.0608

Hom.:

Bravo

AF:

0.0784

Asia WGS

AF:

0.0910

AC:

315

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

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

- -

Apr 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.9

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over