rs2069542

Variant names:

• chr14-23431585-G-A
• rs2069542
• NM_000257.4:c.732C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23431585-G-A
• chr14-23431585-G-C

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.732C>T (p.Phe244=) variant in the MYH7 gene is 53.63% (5704/10406) 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/CA016723/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.27 (7679 hom., cov: 32)
  • Exomes 𝑓: 0.16 (23467 hom.)
• Consequence: MYH7 NM_000257.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0008311
• Clinical Significance: Benign reviewed by expert panel U:1 B:22
• Conservation: PhyloP100: 0.0810
• Publications: 26 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.732C>T	p.Phe244Phe	splice_region synonymous	Exon 8 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.732C>T	p.Phe244Phe	splice_region synonymous	Exon 7 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.732C>T	p.Phe244Phe	splice_region synonymous	Exon 8 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.732C>T	p.Phe244Phe	splice_region synonymous	Exon 8 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.732C>T	p.Phe244Phe	splice_region synonymous	Exon 8 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40281 AN: 152108 Hom.: 7658 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0735

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.246

GnomAD2 exomes AF: 0.175 AC: 44019 AN: 251490 AF XY: 0.173

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.0701

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.165 AC: 240991 AN: 1461880 Hom.: 23467 Cov.: 35 AF XY: 0.165 AC XY: 120195 AN XY: 727240

African (AFR) AF: 0.557 AC: 18655 AN: 33480

American (AMR) AF: 0.122 AC: 5473 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5696 AN: 26136

East Asian (EAS) AF: 0.0498 AC: 1977 AN: 39698

South Asian (SAS) AF: 0.188 AC: 16174 AN: 86258

European-Finnish (FIN) AF: 0.115 AC: 6117 AN: 53420

Middle Eastern (MID) AF: 0.259 AC: 1496 AN: 5768

European-Non Finnish (NFE) AF: 0.157 AC: 174033 AN: 1112000

Other (OTH) AF: 0.188 AC: 11370 AN: 60396

GnomAD4 genome AF: 0.265 AC: 40342 AN: 152226 Hom.: 7679 Cov.: 32 AF XY: 0.257 AC XY: 19109 AN XY: 74452

African (AFR) AF: 0.545 AC: 22627 AN: 41512

American (AMR) AF: 0.181 AC: 2770 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3472

East Asian (EAS) AF: 0.0737 AC: 382 AN: 5184

South Asian (SAS) AF: 0.187 AC: 901 AN: 4826

European-Finnish (FIN) AF: 0.109 AC: 1157 AN: 10618

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10897 AN: 67998

Other (OTH) AF: 0.252 AC: 532 AN: 2112

Alfa AF: 0.213 Hom.: 7002

Bravo AF: 0.279

Asia WGS AF: 0.171 AC: 591 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	1	3	not provided (4)
-	-	3	Cardiomyopathy (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1S (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	-0.35
CADD	Benign	2.4
DANN	Benign	0.86
PhyloP100		0.081
Mutation Taster		=51/49	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00083
dbscSNV1_RF	Benign	0.10
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: rs2069542; hg19: chr14-23900794; COSMIC: COSV62521944;