NM_002471.4:c.393G>A

Variant names:

• chr14-23405332-C-T
• rs17277970
• NM_002471.4:c.393G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):​c.393G>A​(p.Leu131Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,614,132 control chromosomes in the GnomAD database, including 5,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (400 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4901 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.92
• Publications: 8 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-23405332-C-T is Benign according to our data. Variant chr14-23405332-C-T is described in ClinVar as Benign. ClinVar VariationId is 44495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0829 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.393G>A	p.Leu131Leu	synonymous	Exon 5 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.393G>A	p.Leu131Leu	synonymous	Exon 5 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.393G>A	p.Leu131Leu	synonymous	Exon 5 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.393G>A	p.Leu131Leu	synonymous	Exon 5 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0697 AC: 10614 AN: 152208 Hom.: 399 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0781

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.0824

GnomAD2 exomes AF: 0.0684 AC: 17198 AN: 251470 AF XY: 0.0718

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.0420

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0131

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0835

Gnomad OTH exome AF: 0.0762

GnomAD4 exome AF: 0.0783 AC: 114515 AN: 1461806 Hom.: 4901 Cov.: 35 AF XY: 0.0791 AC XY: 57502 AN XY: 727208

African (AFR) AF: 0.0603 AC: 2020 AN: 33474

American (AMR) AF: 0.0435 AC: 1943 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2930 AN: 26136

East Asian (EAS) AF: 0.00957 AC: 380 AN: 39700

South Asian (SAS) AF: 0.0817 AC: 7043 AN: 86256

European-Finnish (FIN) AF: 0.0490 AC: 2620 AN: 53420

Middle Eastern (MID) AF: 0.0920 AC: 530 AN: 5760

European-Non Finnish (NFE) AF: 0.0829 AC: 92199 AN: 1111958

Other (OTH) AF: 0.0803 AC: 4850 AN: 60384

GnomAD4 genome AF: 0.0697 AC: 10613 AN: 152326 Hom.: 400 Cov.: 32 AF XY: 0.0670 AC XY: 4992 AN XY: 74482

African (AFR) AF: 0.0593 AC: 2465 AN: 41572

American (AMR) AF: 0.0517 AC: 792 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3472

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5186

South Asian (SAS) AF: 0.0781 AC: 377 AN: 4826

European-Finnish (FIN) AF: 0.0498 AC: 529 AN: 10622

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0847 AC: 5763 AN: 68024

Other (OTH) AF: 0.0820 AC: 173 AN: 2110

Alfa AF: 0.0805 Hom.: 205

Bravo AF: 0.0694

Asia WGS AF: 0.0420 AC: 147 AN: 3478

EpiCase AF: 0.0926

EpiControl AF: 0.0899

ClinVar

ClinVar submissions

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	-0.33
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		1.9
Mutation Taster		=92/8	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: rs17277970; hg19: chr14-23874541; COSMIC: COSV62448852;