NM_002471.4:c.427C>A

Variant names:

• chr14-23405298-G-T
• rs2277473
• NM_002471.4:c.427C>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.427C>A​(p.Arg143Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,614,114 control chromosomes in the GnomAD database, including 8,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (681 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7691 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.496
• Publications: 15 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=-0.38).
• BP6: Variant 14-23405298-G-T is Benign according to our data. Variant chr14-23405298-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.496 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 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.427C>A	p.Arg143Arg	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.427C>A	p.Arg143Arg	synonymous	Exon 5 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.427C>A	p.Arg143Arg	synonymous	Exon 5 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.427C>A	p.Arg143Arg	synonymous	Exon 5 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0826 AC: 12563 AN: 152158 Hom.: 681 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0932

GnomAD2 exomes AF: 0.0955 AC: 24013 AN: 251488 AF XY: 0.101

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.0706

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.0558

Gnomad FIN exome AF: 0.0920

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0996 AC: 145564 AN: 1461838 Hom.: 7691 Cov.: 35 AF XY: 0.102 AC XY: 73864 AN XY: 727218

African (AFR) AF: 0.0183 AC: 611 AN: 33476

American (AMR) AF: 0.0734 AC: 3284 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3252 AN: 26136

East Asian (EAS) AF: 0.0474 AC: 1882 AN: 39700

South Asian (SAS) AF: 0.143 AC: 12364 AN: 86254

European-Finnish (FIN) AF: 0.0937 AC: 5007 AN: 53414

Middle Eastern (MID) AF: 0.121 AC: 695 AN: 5764

European-Non Finnish (NFE) AF: 0.101 AC: 112536 AN: 1111988

Other (OTH) AF: 0.0983 AC: 5933 AN: 60386

GnomAD4 genome AF: 0.0824 AC: 12553 AN: 152276 Hom.: 681 Cov.: 32 AF XY: 0.0826 AC XY: 6152 AN XY: 74466

African (AFR) AF: 0.0229 AC: 951 AN: 41544

American (AMR) AF: 0.108 AC: 1648 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 439 AN: 3472

East Asian (EAS) AF: 0.0563 AC: 292 AN: 5184

South Asian (SAS) AF: 0.140 AC: 673 AN: 4824

European-Finnish (FIN) AF: 0.0895 AC: 950 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7105 AN: 68012

Other (OTH) AF: 0.0918 AC: 194 AN: 2114

Alfa AF: 0.0608 Hom.: 98

Bravo AF: 0.0784

Asia WGS AF: 0.0910 AC: 315 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.9
DANN	Benign	0.68
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2277473; hg19: chr14-23874507;