rs61731179

Positions:

• chr14-23400784-G-A

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.1335C>T​(p.Asn445=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,614,236 control chromosomes in the GnomAD database, including 2,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (189 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2689 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.334

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=-0.46).
• BP6: Variant 14-23400784-G-A is Benign according to our data. Variant chr14-23400784-G-A is described in ClinVar as [Benign]. Clinvar id is 44451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23400784-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.334 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.1335C>T	p.Asn445=	synonymous_variant	13/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.1335C>T	p.Asn445=	synonymous_variant	13/39	5	NM_002471.4	P1
MYH6	ENST00000557461.2	n.1402C>T		non_coding_transcript_exon_variant	13/14	5

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6308 AN: 152228 Hom.: 189 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0540

GnomAD3 exomes AF: 0.0532 AC: 13369 AN: 251486 Hom.: 468 AF XY: 0.0571 AC XY: 7756 AN XY: 135922

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0781

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0861

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0636

Gnomad OTH exome AF: 0.0692

GnomAD4 exome AF: 0.0560 AC: 81847 AN: 1461890 Hom.: 2689 Cov.: 32 AF XY: 0.0576 AC XY: 41858 AN XY: 727246

Gnomad4 AFR exome AF: 0.00869

Gnomad4 AMR exome AF: 0.0328

Gnomad4 ASJ exome AF: 0.0800

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0885

Gnomad4 FIN exome AF: 0.0495

Gnomad4 NFE exome AF: 0.0574

Gnomad4 OTH exome AF: 0.0546

GnomAD4 genome AF: 0.0414 AC: 6307 AN: 152346 Hom.: 189 Cov.: 32 AF XY: 0.0414 AC XY: 3081 AN XY: 74488

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.0391

Gnomad4 ASJ AF: 0.0873

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0737

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0590

Gnomad4 OTH AF: 0.0534

Alfa AF: 0.0533 Hom.: 130

Bravo AF: 0.0403

EpiCase AF: 0.0674

EpiControl AF: 0.0662

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	PreventionGenetics, part of Exact Sciences	-	- -
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	Sep 27, 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	Dec 02, 2011	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 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	-0.46
CADD	Benign	6.9
DANN	Benign	0.79

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: rs61731179; hg19: chr14-23869993;