Genetic Variant MYH6:c.4651-17G>A (chr14-23386640-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002471.4(MYH6):c.4651-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,461,826 control chromosomes in the GnomAD database, including 53,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4408 hom., cov: 30)

Exomes 𝑓: 0.28 ( 49100 hom. )

Consequence

MYH6
NM_002471.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.10

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 14-23386640-C-T is Benign according to our data. Variant chr14-23386640-C-T is described in ClinVar as [Benign]. Clinvar id is 258711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23386640-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.4651-17G>A		intron_variant	Intron 32 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.4651-17G>A		intron_variant	Intron 32 of 38	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

35818

AN:

150064

Hom.:

4403

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.363

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.280

GnomAD3 exomes

AF:

0.249

AC:

59829

AN:

240322

Hom.:

8035

AF XY:

0.260

AC XY:

33732

AN XY:

129530

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.178

Gnomad SAS exome

AF:

0.358

Gnomad FIN exome

AF:

0.216

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.279

AC:

366391

AN:

1311638

Hom.:

49100

Cov.:

AF XY:

0.282

AC XY:

184800

AN XY:

654186

show subpopulations

Gnomad4 AFR exome

AF:

0.203

Gnomad4 AMR exome

AF:

0.187

Gnomad4 ASJ exome

AF:

0.349

Gnomad4 EAS exome

AF:

0.201

Gnomad4 SAS exome

AF:

0.360

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.282

Gnomad4 OTH exome

AF:

0.277

GnomAD4 genome

AF:

0.239

AC:

35850

AN:

150188

Hom.:

4408

Cov.:

AF XY:

0.238

AC XY:

17506

AN XY:

73406

show subpopulations

Gnomad4 AFR

AF:

0.190

Gnomad4 AMR

AF:

0.243

Gnomad4 ASJ

AF:

0.342

Gnomad4 EAS

AF:

0.188

Gnomad4 SAS

AF:

0.363

Gnomad4 FIN

AF:

0.222

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.284

Alfa

AF:

0.247

Hom.:

918

Bravo

AF:

0.234

Asia WGS

AF:

0.261

AC:

908

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.054

DANN

Benign

0.76

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