rs17091623

chr14-23402790-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):c.909G>A(p.Leu303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,611,546 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (158 hom., cov: 30)
  • Exomes 𝑓: 0.0033 (156 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.497

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 14-23402790-C-T is Benign according to our data. Variant chr14-23402790-C-T is described in ClinVar as [Benign]. Clinvar id is 44546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23402790-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.497 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.909G>A	p.Leu303=	synonymous_variant	11/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.909G>A	p.Leu303=	synonymous_variant	11/39	5	NM_002471.4	P1
MYH6	ENST00000557461.2	n.976G>A		non_coding_transcript_exon_variant	11/14	5

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3806 AN: 150050 Hom.: 158 Cov.: 30

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00882

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000797

Gnomad OTH AF: 0.0247

GnomAD3 exomes AF: 0.00825 AC: 2066 AN: 250314 Hom.: 78 AF XY: 0.00681 AC XY: 921 AN XY: 135326

Gnomad AFR exome AF: 0.0914

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00892

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000576

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00330 AC: 4822 AN: 1461374 Hom.: 156 Cov.: 33 AF XY: 0.00318 AC XY: 2313 AN XY: 726974

Gnomad4 AFR exome AF: 0.0882

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00880

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.0254 AC: 3813 AN: 150172 Hom.: 158 Cov.: 30 AF XY: 0.0245 AC XY: 1792 AN XY: 73122

Gnomad4 AFR AF: 0.0857

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00882

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000797

Gnomad4 OTH AF: 0.0244

Alfa AF: 0.00719 Hom.: 63

Bravo AF: 0.0297

Asia WGS AF: 0.0110 AC: 40 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000533

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	GeneDx	Oct 25, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 31, 2012	8.7% (324/3738) of Afr Amer chrom in ESP. -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 06, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 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	-0.41
Cadd	Benign	12
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17091623; hg19: chr14-23871999;