rs141704264

chr14-23393788-C-Achr14-23393788-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):c.2806G>T(p.Ala936Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,614,230 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A936V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0077 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (6 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.84

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=0.0063937604).
• BP6: Variant 14-23393788-C-A is Benign according to our data. Variant chr14-23393788-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 44471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23393788-C-A is described in Lovd as [Benign]. Variant chr14-23393788-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00773 (1177/152336) while in subpopulation AFR AF= 0.0252 (1046/41572). AF 95% confidence interval is 0.0239. There are 23 homozygotes in gnomad4. There are 537 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.2806G>T	p.Ala936Ser	missense_variant	22/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.2806G>T	p.Ala936Ser	missense_variant	22/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152218 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00214 AC: 537 AN: 251494 Hom.: 6 AF XY: 0.00149 AC XY: 203 AN XY: 135920

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000770 AC: 1125 AN: 1461894 Hom.: 6 Cov.: 33 AF XY: 0.000671 AC XY: 488 AN XY: 727248

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00773 AC: 1177 AN: 152336 Hom.: 23 Cov.: 32 AF XY: 0.00721 AC XY: 537 AN XY: 74490

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.000933 Hom.: 1

Bravo AF: 0.00851

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0256 AC: 113

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 23, 2012	Ala936Ser in exon 22 of MYH6: This variant has been identified in 2.6% (99/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs141704264). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;.
MetaRNN	Benign	0.0064	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.27
Sift	Benign	0.33	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.21	B;B
Vest4		0.21
MVP		0.93
MPC		0.44
ClinPred		0.015	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.82

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: rs141704264; hg19: chr14-23862997; COSMIC: COSV62453344;