rs2069543

Variant names:

• chr14-23427868-T-C
• rs2069543
• NM_000257.4:c.1605A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-23427868-T-C
• chr14-23427868-T-G
• chr14-23427868-T-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1605A>G (p.Glu535=) variant in the MYH7 gene is 10.63% (1162/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). LINK:https://erepo.genome.network/evrepo/ui/classification/CA011032/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.031 (238 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (216 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: 0.328
• Publications: 2 publications found

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.1605A>G	p.Glu535Glu	synonymous	Exon 16 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.1605A>G	p.Glu535Glu	synonymous	Exon 15 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.1605A>G	p.Glu535Glu	synonymous	Exon 16 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.1605A>G	p.Glu535Glu	synonymous	Exon 16 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.1605A>G	p.Glu535Glu	synonymous	Exon 16 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4657 AN: 152104 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00829 AC: 2084 AN: 251372 AF XY: 0.00622

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00341 AC: 4987 AN: 1461888 Hom.: 216 Cov.: 32 AF XY: 0.00305 AC XY: 2217 AN XY: 727248

African (AFR) AF: 0.109 AC: 3662 AN: 33480

American (AMR) AF: 0.00646 AC: 289 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5764

European-Non Finnish (NFE) AF: 0.000380 AC: 423 AN: 1112012

Other (OTH) AF: 0.00808 AC: 488 AN: 60396

GnomAD4 genome AF: 0.0307 AC: 4670 AN: 152222 Hom.: 238 Cov.: 32 AF XY: 0.0298 AC XY: 2221 AN XY: 74418

African (AFR) AF: 0.106 AC: 4409 AN: 41504

American (AMR) AF: 0.0100 AC: 153 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.0219 Hom.: 77

Bravo AF: 0.0351

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	Cardiomyopathy (4)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.9
DANN	Benign	0.57
PhyloP100		0.33
Mutation Taster		=63/37	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2069543; hg19: chr14-23897077;