rs45574136

Variant names:

• chr14-23386496-T-A
• rs45574136
• NM_002471.4:c.4778A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.4778A>T​(p.Gln1593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,612,108 control chromosomes in the GnomAD database, including 592 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (311 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (281 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.99
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018672347).
• BP6: Variant 14-23386496-T-A is Benign according to our data. Variant chr14-23386496-T-A is described in ClinVar as Benign. ClinVar VariationId is 44520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 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.4778A>T	p.Gln1593Leu	missense	Exon 33 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.4778A>T	p.Gln1593Leu	missense	Exon 33 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4811A>T	p.Gln1604Leu	missense	Exon 33 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.4778A>T	p.Gln1593Leu	missense	Exon 33 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5620 AN: 152076 Hom.: 311 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0113 AC: 2834 AN: 250484 AF XY: 0.00958

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0148

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.00735 AC: 10728 AN: 1459914 Hom.: 281 Cov.: 70 AF XY: 0.00681 AC XY: 4943 AN XY: 726266

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.111 AC: 3666 AN: 32932

American (AMR) AF: 0.00957 AC: 427 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26128

East Asian (EAS) AF: 0.0124 AC: 492 AN: 39672

South Asian (SAS) AF: 0.00632 AC: 544 AN: 86120

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53418

Middle Eastern (MID) AF: 0.00574 AC: 33 AN: 5748

European-Non Finnish (NFE) AF: 0.00433 AC: 4810 AN: 1111002

Other (OTH) AF: 0.0117 AC: 708 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0370 AC: 5637 AN: 152194 Hom.: 311 Cov.: 31 AF XY: 0.0356 AC XY: 2650 AN XY: 74410

African (AFR) AF: 0.118 AC: 4898 AN: 41484

American (AMR) AF: 0.0144 AC: 221 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0167 AC: 86 AN: 5164

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00479 AC: 326 AN: 68004

Other (OTH) AF: 0.0255 AC: 54 AN: 2116

Alfa AF: 0.0131 Hom.: 19

Bravo AF: 0.0429

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.0149 AC: 1805

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.4
DANN	Benign	0.76
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Benign	0.82	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.089
MPC		0.25
ClinPred		0.0049	T
GERP RS		1.8
Varity_R		0.081
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45574136; hg19: chr14-23855705; COSMIC: COSV62451118; COSMIC: COSV62451118;