chr14-23433544-G-A

Variant names:

• chr14-23433544-G-A
• rs2069540
• NM_000257.4:c.189C>T

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.189C>T (p.Thr63=) variant in the MYH7 gene is 61.57% (6532/10394) 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/CA011440/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.51 (20612 hom., cov: 33)
  • Exomes 𝑓: 0.48 (171870 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:27
• Conservation: PhyloP100: -7.38
• 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

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.189C>T	p.Thr63Thr	synonymous	Exon 3 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.189C>T	p.Thr63Thr	synonymous	Exon 2 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.189C>T	p.Thr63Thr	synonymous	Exon 3 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.189C>T	p.Thr63Thr	synonymous	Exon 3 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.189C>T	p.Thr63Thr	synonymous	Exon 3 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78208 AN: 151956 Hom.: 20601 Cov.: 33

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.481 AC: 120879 AN: 251254 AF XY: 0.487

Gnomad AFR exome AF: 0.625

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.482 AC: 704055 AN: 1461464 Hom.: 171870 Cov.: 52 AF XY: 0.485 AC XY: 352326 AN XY: 727056

African (AFR) AF: 0.628 AC: 21029 AN: 33472

American (AMR) AF: 0.433 AC: 19354 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12129 AN: 26136

East Asian (EAS) AF: 0.319 AC: 12677 AN: 39698

South Asian (SAS) AF: 0.586 AC: 50511 AN: 86244

European-Finnish (FIN) AF: 0.415 AC: 22149 AN: 53344

Middle Eastern (MID) AF: 0.523 AC: 2972 AN: 5688

European-Non Finnish (NFE) AF: 0.480 AC: 533604 AN: 1111790

Other (OTH) AF: 0.491 AC: 29630 AN: 60370

GnomAD4 genome AF: 0.515 AC: 78272 AN: 152074 Hom.: 20612 Cov.: 33 AF XY: 0.508 AC XY: 37795 AN XY: 74340

African (AFR) AF: 0.627 AC: 26004 AN: 41470

American (AMR) AF: 0.473 AC: 7228 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1636 AN: 3470

East Asian (EAS) AF: 0.386 AC: 1990 AN: 5152

South Asian (SAS) AF: 0.580 AC: 2798 AN: 4824

European-Finnish (FIN) AF: 0.392 AC: 4149 AN: 10582

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32627 AN: 67978

Other (OTH) AF: 0.506 AC: 1065 AN: 2104

Alfa AF: 0.490 Hom.: 80929

Bravo AF: 0.521

Asia WGS AF: 0.499 AC: 1737 AN: 3478

EpiCase AF: 0.491

EpiControl AF: 0.487

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	Cardiomyopathy (3)
-	-	3	Myosin storage myopathy (3)
-	-	2	Dilated cardiomyopathy 1S (2)
-	-	2	MYH7-related skeletal myopathy (2)
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Myopathy, myosin storage, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.31
DANN	Benign	0.79
PhyloP100		-7.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2069540; hg19: chr14-23902753; COSMIC: COSV62519294;