rs45574136

chr14-23386496-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):c.4778A>T(p.Gln1593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,612,108 control chromosomes in the GnomAD database, including 592 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (311 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (281 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.99

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.

• PP2: Missense variant where missense usually causes diseases, MYH6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018672347).
• BP6: Variant 14-23386496-T-A is Benign according to our data. Variant chr14-23386496-T-A is described in ClinVar as [Benign]. Clinvar id is 44520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23386496-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.4778A>T	p.Gln1593Leu	missense_variant	33/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.4778A>T	p.Gln1593Leu	missense_variant	33/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5620 AN: 152076 Hom.: 311 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0113 AC: 2834 AN: 250484 Hom.: 129 AF XY: 0.00958 AC XY: 1298 AN XY: 135464

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0148

Gnomad SAS exome AF: 0.00537

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.00735 AC: 10728 AN: 1459914 Hom.: 281 Cov.: 70 AF XY: 0.00681 AC XY: 4943 AN XY: 726266

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.00957

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.00632

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0370 AC: 5637 AN: 152194 Hom.: 311 Cov.: 31 AF XY: 0.0356 AC XY: 2650 AN XY: 74410

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0167

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00479

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0131 Hom.: 19

Bravo AF: 0.0429

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.0149 AC: 1805

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 15, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2011	- -
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	Oct 24, 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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Jul 08, 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
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	9.4
Dann	Benign	0.76
DEOGEN2	Uncertain	0.66	D;D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.22	T;.
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.22
Sift	Benign	0.82	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0	B;B
Vest4		0.089
MPC		0.25
ClinPred		0.0049	T
GERP RS		1.8
Varity_R		0.081
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45574136; hg19: chr14-23855705; COSMIC: COSV62451118; COSMIC: COSV62451118;