rs2284651

Variant names:

• chr14-23412935-T-C
• rs2284651
• NM_000257.4:c.5791-64A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-23412935-T-C
• chr14-23412935-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000257.4(MYH7):​c.5791-64A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,562,884 control chromosomes in the GnomAD database, including 115,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16634 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98491 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.89
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-23412935-T-C is Benign according to our data. Variant chr14-23412935-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5791-64A>G		intron_variant	Intron 39 of 39	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5791-64A>G		intron_variant	Intron 38 of 38		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5791-64A>G		intron_variant	Intron 39 of 39	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.*32-64A>G		intron_variant	Intron 40 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5791-64A>G		intron_variant	Intron 38 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66576 AN: 151902 Hom.: 16591 Cov.: 32

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.449

GnomAD4 exome AF: 0.364 AC: 514117 AN: 1410864 Hom.: 98491 AF XY: 0.361 AC XY: 254578 AN XY: 704664

African (AFR) AF: 0.696 AC: 22606 AN: 32482

American (AMR) AF: 0.237 AC: 10519 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 11302 AN: 25826

East Asian (EAS) AF: 0.136 AC: 5366 AN: 39412

South Asian (SAS) AF: 0.271 AC: 23100 AN: 85092

European-Finnish (FIN) AF: 0.280 AC: 14416 AN: 51450

Middle Eastern (MID) AF: 0.377 AC: 2146 AN: 5692

European-Non Finnish (NFE) AF: 0.377 AC: 402773 AN: 1067728

Other (OTH) AF: 0.372 AC: 21889 AN: 58814

GnomAD4 genome AF: 0.439 AC: 66666 AN: 152020 Hom.: 16634 Cov.: 32 AF XY: 0.426 AC XY: 31666 AN XY: 74322

African (AFR) AF: 0.687 AC: 28487 AN: 41460

American (AMR) AF: 0.316 AC: 4824 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1478 AN: 3466

East Asian (EAS) AF: 0.154 AC: 795 AN: 5158

South Asian (SAS) AF: 0.268 AC: 1289 AN: 4818

European-Finnish (FIN) AF: 0.269 AC: 2846 AN: 10572

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25482 AN: 67950

Other (OTH) AF: 0.452 AC: 954 AN: 2110

Alfa AF: 0.356 Hom.: 2265

Bravo AF: 0.452

Asia WGS AF: 0.272 AC: 947 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.075
DANN	Benign	0.53
PhyloP100		-2.9
Mutation Taster		=100/0	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: rs2284651; hg19: chr14-23882144; COSMIC: COSV62519821; COSMIC: COSV62519821;