rs2277474

Variant names:

• chr14-23405314-C-T
• rs2277474
• NM_002471.4:c.411G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-23405314-C-T
• chr14-23405314-C-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.411G>A​(p.Glu137Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,614,008 control chromosomes in the GnomAD database, including 48,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3915 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44921 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.342
• Publications: 19 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=-0.41).
• BP6: Variant 14-23405314-C-T is Benign according to our data. Variant chr14-23405314-C-T is described in ClinVar as Benign. ClinVar VariationId is 44504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.342 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 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.411G>A	p.Glu137Glu	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.411G>A	p.Glu137Glu	synonymous	Exon 5 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.411G>A	p.Glu137Glu	synonymous	Exon 5 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.411G>A	p.Glu137Glu	synonymous	Exon 5 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33077 AN: 152074 Hom.: 3916 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.0561

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.207 AC: 52054 AN: 251464 AF XY: 0.212

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.0561

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.243 AC: 354887 AN: 1461816 Hom.: 44921 Cov.: 59 AF XY: 0.242 AC XY: 175697 AN XY: 727210

African (AFR) AF: 0.167 AC: 5590 AN: 33474

American (AMR) AF: 0.133 AC: 5949 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7774 AN: 26136

East Asian (EAS) AF: 0.0475 AC: 1887 AN: 39700

South Asian (SAS) AF: 0.188 AC: 16210 AN: 86252

European-Finnish (FIN) AF: 0.219 AC: 11694 AN: 53414

Middle Eastern (MID) AF: 0.213 AC: 1229 AN: 5764

European-Non Finnish (NFE) AF: 0.261 AC: 290331 AN: 1111970

Other (OTH) AF: 0.236 AC: 14223 AN: 60386

GnomAD4 genome AF: 0.217 AC: 33090 AN: 152192 Hom.: 3915 Cov.: 32 AF XY: 0.215 AC XY: 15962 AN XY: 74414

African (AFR) AF: 0.170 AC: 7054 AN: 41524

American (AMR) AF: 0.194 AC: 2972 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1038 AN: 3472

East Asian (EAS) AF: 0.0564 AC: 292 AN: 5178

South Asian (SAS) AF: 0.179 AC: 861 AN: 4820

European-Finnish (FIN) AF: 0.210 AC: 2225 AN: 10602

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17764 AN: 67986

Other (OTH) AF: 0.221 AC: 467 AN: 2112

Alfa AF: 0.243 Hom.: 7436

Bravo AF: 0.211

Asia WGS AF: 0.122 AC: 423 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.266

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.41
CADD	Benign	7.0
DANN	Benign	0.55
PhyloP100		0.34
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: rs2277474; hg19: chr14-23874523; COSMIC: COSV62453843;