rs201193346

Variant names:

• chr14-23394139-G-A
• rs201193346
• NM_002471.4:c.2614C>T
• MYH6 p.Arg872Cys

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002471.4(MYH6):​c.2614C>T​(p.Arg872Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R872H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 1.66
• 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):

• 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 -9 ACMG points.

• BP6: Variant 14-23394139-G-A is Benign according to our data. Variant chr14-23394139-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44470.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152292) while in subpopulation SAS AF = 0.00124 (6/4828). AF 95% confidence interval is 0.000541. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 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.2614C>T	p.Arg872Cys	missense	Exon 21 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.2614C>T	p.Arg872Cys	missense	Exon 21 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.2647C>T	p.Arg883Cys	missense	Exon 21 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.2614C>T	p.Arg872Cys	missense	Exon 21 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000314 AC: 79 AN: 251458 AF XY: 0.000375

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000486 AC: 711 AN: 1461880 Hom.: 1 Cov.: 33 AF XY: 0.000468 AC XY: 340 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

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

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

South Asian (SAS) AF: 0.000904 AC: 78 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53408

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000522 AC: 580 AN: 1112012

Other (OTH) AF: 0.000530 AC: 32 AN: 60396

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74466

African (AFR) AF: 0.0000962 AC: 4 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000472 Hom.: 1

Bravo AF: 0.000264

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		1.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.041	D
Varity_R		0.49
gMVP		0.97
Mutation Taster		=55/45	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201193346;

hg19: chr14-23863348;

COSMIC: COSV62452135;