rs17091278

chr14-23383288-T-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.5598A>G(p.Leu1866=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,395,506 control chromosomes in the GnomAD database, including 2,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1216 hom., cov: 29)
  • Exomes 𝑓: 0.014 (1115 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.30

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=-0.54).
• BP6: Variant 14-23383288-T-C is Benign according to our data. Variant chr14-23383288-T-C is described in ClinVar as [Benign]. Clinvar id is 258715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23383288-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.5598A>G	p.Leu1866=	synonymous_variant	37/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.5598A>G	p.Leu1866=	synonymous_variant	37/39	5	NM_002471.4	P1
MYH6	ENST00000651452.1	n.825A>G		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.0833 AC: 10576 AN: 126896 Hom.: 1205 Cov.: 29

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0439

Gnomad ASJ AF: 0.00182

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.00950

Gnomad FIN AF: 0.000182

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.00555

Gnomad OTH AF: 0.0580

GnomAD3 exomes AF: 0.0227 AC: 5698 AN: 251254 Hom.: 524 AF XY: 0.0179 AC XY: 2432 AN XY: 135806

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0169

Gnomad SAS exome AF: 0.00683

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0135 AC: 17136 AN: 1268540 Hom.: 1115 Cov.: 36 AF XY: 0.0122 AC XY: 7687 AN XY: 628584

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0235

Gnomad4 SAS exome AF: 0.00686

Gnomad4 FIN exome AF: 0.000426

Gnomad4 NFE exome AF: 0.00560

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0836 AC: 10614 AN: 126966 Hom.: 1216 Cov.: 29 AF XY: 0.0861 AC XY: 5050 AN XY: 58668

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.0437

Gnomad4 ASJ AF: 0.00182

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.00926

Gnomad4 FIN AF: 0.000182

Gnomad4 NFE AF: 0.00555

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0368 Hom.: 231

Bravo AF: 0.0829

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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. -
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	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	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 16, 2016	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 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	-0.54
Cadd	Benign	4.6
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

Other links and lift over

dbSNP: rs17091278; hg19: chr14-23852497; COSMIC: COSV59306088; COSMIC: COSV59306088;