rs17091278

Variant names:

• chr14-23383288-T-C
• rs17091278
• NM_002471.4:c.5598A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):​c.5598A>G​(p.Leu1866Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,395,506 control chromosomes in the GnomAD database, including 2,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1216 hom., cov: 29)
  • Exomes 𝑓: 0.014 (1115 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.30
• Publications: 5 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):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• 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: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 14-23383288-T-C is Benign according to our data. Variant chr14-23383288-T-C is described in ClinVar as Benign. ClinVar VariationId is 258715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.5598A>G	p.Leu1866Leu	synonymous	Exon 37 of 39	NP_002462.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.5598A>G	p.Leu1866Leu	synonymous	Exon 37 of 39	ENSP00000386041.3
	MYH6	ENST00000651452.1		n.825A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0833 AC: 10576 AN: 126896 Hom.: 1205 Cov.: 29

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0439

Gnomad ASJ AF: 0.00182

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.00950

Gnomad FIN AF: 0.000182

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.00555

Gnomad OTH AF: 0.0580

GnomAD2 exomes AF: 0.0227 AC: 5698 AN: 251254 AF XY: 0.0179

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0169

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0135 AC: 17136 AN: 1268540 Hom.: 1115 Cov.: 36 AF XY: 0.0122 AC XY: 7687 AN XY: 628584

African (AFR) AF: 0.275 AC: 8285 AN: 30158

American (AMR) AF: 0.0209 AC: 820 AN: 39222

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 39 AN: 18822

East Asian (EAS) AF: 0.0235 AC: 506 AN: 21556

South Asian (SAS) AF: 0.00686 AC: 578 AN: 84260

European-Finnish (FIN) AF: 0.000426 AC: 16 AN: 37534

Middle Eastern (MID) AF: 0.0151 AC: 58 AN: 3846

European-Non Finnish (NFE) AF: 0.00560 AC: 5519 AN: 985158

Other (OTH) AF: 0.0274 AC: 1315 AN: 47984

GnomAD4 genome AF: 0.0836 AC: 10614 AN: 126966 Hom.: 1216 Cov.: 29 AF XY: 0.0861 AC XY: 5050 AN XY: 58668

African (AFR) AF: 0.273 AC: 9632 AN: 35316

American (AMR) AF: 0.0437 AC: 399 AN: 9134

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 6 AN: 3288

East Asian (EAS) AF: 0.0216 AC: 83 AN: 3838

South Asian (SAS) AF: 0.00926 AC: 35 AN: 3780

European-Finnish (FIN) AF: 0.000182 AC: 1 AN: 5494

Middle Eastern (MID) AF: 0.0275 AC: 6 AN: 218

European-Non Finnish (NFE) AF: 0.00555 AC: 351 AN: 63276

Other (OTH) AF: 0.0577 AC: 101 AN: 1750

Alfa AF: 0.0368 Hom.: 231

Bravo AF: 0.0829

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00445

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.6
DANN	Benign	0.76
PhyloP100		-1.3
Mutation Taster		=94/6	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: rs17091278; hg19: chr14-23852497; COSMIC: COSV59306088; COSMIC: COSV59306088;