14-23405642-C-T

Position:

chr14-23405642-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002471.4(MYH6):c.330G>A(p.Ala110Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,614,156 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 33 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -5.42

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:

MYH6 (HGNC:):

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

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

BP6

Variant 14-23405642-C-T is Benign according to our data. Variant chr14-23405642-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23405642-C-T is described in Lovd as [Benign]. Variant chr14-23405642-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-5.42 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00464 (706/152270) while in subpopulation NFE AF= 0.00694 (472/68004). AF 95% confidence interval is 0.00642. There are 4 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 706 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.330G>A	p.Ala110Ala	synonymous_variant	4/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.330G>A	p.Ala110Ala	synonymous_variant	4/39	5	NM_002471.4	ENSP00000386041.3		P13533
MYH6	ENST00000557461.2 linkuse as main transcript	n.397G>A		non_coding_transcript_exon_variant	4/14	5

Frequencies

GnomAD3 genomes

AF:

0.00464

AC:

706

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00866

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00694

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00388

AC:

975

AN:

251422

Hom.:

AF XY:

0.00386

AC XY:

525

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00771

Gnomad NFE exome

AF:

0.00609

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00574

AC:

8392

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

4016

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00728

Gnomad4 NFE exome

AF:

0.00670

Gnomad4 OTH exome

AF:

0.00573

GnomAD4 genome

AF:

0.00464

AC:

706

AN:

152270

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00866

Gnomad4 NFE

AF:

0.00694

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00495

Hom.:

Bravo

AF:

0.00374

EpiCase

AF:

0.00545

EpiControl

AF:

0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2012	Ala110Ala in exon 4 of MYH6: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 0.5% (35/7020) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs77679218). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2017	Variant summary: The MYH6 c.330G>A (p.Ala110Ala) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1116/277156 control chromosomes at a frequency of 0.0040266, which is approximately 161 times the estimated maximal expected allele frequency of a pathogenic MYH6 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2016	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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 16, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MYH6: BP4, BP7, BS1, BS2 -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 30, 2015

- -

MYH6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2016

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

0.12

DANN

Benign

0.83

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

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