NM_002471.4:c.5796G>A

Variant names:

• chr14-23382428-C-T
• rs730880153
• NM_002471.4:c.5796G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_002471.4(MYH6):​c.5796G>A​(p.Lys1932Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000821 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MYH6 NM_002471.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.92
• Publications: 0 publications found

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

• MYH-6 related congenital heart defects

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. 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
	MYH6	NM_002471.4	MANE Select	c.5796G>A	p.Lys1932Lys	splice_region synonymous	Exon 38 of 39	NP_002462.2	P13533

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.5796G>A	p.Lys1932Lys	splice_region synonymous	Exon 38 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.5829G>A	p.Lys1943Lys	splice_region synonymous	Exon 38 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.5820G>A	p.Lys1940Lys	splice_region synonymous	Exon 38 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251472 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	AV Block Third Degree Adverse Event (1)
-	1	-	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.87
PhyloP100		4.9
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.39		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730880153; hg19: chr14-23851637;