rs2069541

Variant names:

• chr14-23431803-T-C
• rs2069541
• NM_000257.4:c.597A>G

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.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European 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/CA016520/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.0087 (9 hom., cov: 33)
  • Exomes 𝑓: 0.014 (178 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:25
• Conservation: PhyloP100: -3.96
• Publications: 6 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.597A>G	p.Ala199Ala	synonymous	Exon 7 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.597A>G	p.Ala199Ala	synonymous	Exon 6 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.597A>G	p.Ala199Ala	synonymous	Exon 7 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.597A>G	p.Ala199Ala	synonymous	Exon 7 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.597A>G	p.Ala199Ala	synonymous	Exon 7 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1331 AN: 152244 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0103 AC: 2580 AN: 251494 AF XY: 0.0112

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0138 AC: 20221 AN: 1461874 Hom.: 178 Cov.: 34 AF XY: 0.0138 AC XY: 10056 AN XY: 727238

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00693 AC: 310 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0125 AC: 1079 AN: 86258

European-Finnish (FIN) AF: 0.00315 AC: 168 AN: 53418

Middle Eastern (MID) AF: 0.0316 AC: 182 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17682 AN: 1111994

Other (OTH) AF: 0.0112 AC: 679 AN: 60396

GnomAD4 genome AF: 0.00874 AC: 1332 AN: 152362 Hom.: 9 Cov.: 33 AF XY: 0.00816 AC XY: 608 AN XY: 74508

African (AFR) AF: 0.00243 AC: 101 AN: 41594

American (AMR) AF: 0.00758 AC: 116 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4820

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10626

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1003 AN: 68036

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0134 Hom.: 45

Bravo AF: 0.00961

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0177

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)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (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	-0.69
CADD	Benign	0.22
DANN	Benign	0.67
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2069541; hg19: chr14-23901012;