rs382872

chr14-23386111-G-Achr14-23386111-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):c.4980C>T(p.Asp1660=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,614,156 control chromosomes in the GnomAD database, including 9,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (539 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8687 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.151

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 14-23386111-G-A is Benign according to our data. Variant chr14-23386111-G-A is described in ClinVar as [Benign]. Clinvar id is 44528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23386111-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.4980C>T	p.Asp1660=	synonymous_variant	34/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.4980C>T	p.Asp1660=	synonymous_variant	34/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.0761 AC: 11578 AN: 152152 Hom.: 538 Cov.: 31

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0546

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0721

GnomAD3 exomes AF: 0.0754 AC: 18958 AN: 251326 Hom.: 921 AF XY: 0.0759 AC XY: 10312 AN XY: 135840

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0386

Gnomad FIN exome AF: 0.0859

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0901

GnomAD4 exome AF: 0.103 AC: 149850 AN: 1461886 Hom.: 8687 Cov.: 35 AF XY: 0.101 AC XY: 73280 AN XY: 727242

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0395

Gnomad4 FIN exome AF: 0.0841

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.0969

GnomAD4 genome AF: 0.0761 AC: 11581 AN: 152270 Hom.: 539 Cov.: 31 AF XY: 0.0746 AC XY: 5553 AN XY: 74438

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.0546

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.0902

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.0714

Alfa AF: 0.101 Hom.: 376

Bravo AF: 0.0727

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.109

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2015

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	-0.60
Cadd	Benign	0.10
Dann	Benign	0.88

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

Other links and lift over

dbSNP: rs382872; hg19: chr14-23855320;