14-23390281-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_002471.4(MYH6):c.3508G>A(p.Glu1170Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,596,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E1170Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 7.55

Publications

3 publications found

Variant links:

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

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 14-23390281-C-T is Benign according to our data. Variant chr14-23390281-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164230.

BS2

High AC in GnomAd4 at 10 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.3508G>A	p.Glu1170Lys	missense	Exon 26 of 39	NP_002462.2	P13533

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3508G>A	p.Glu1170Lys	missense	Exon 26 of 39	ENSP00000386041.3	P13533
MYH6	ENST00000968262.1		c.3541G>A	p.Glu1181Lys	missense	Exon 26 of 39	ENSP00000638321.1
MYH6	ENST00000968257.1		c.3508G>A	p.Glu1170Lys	missense	Exon 26 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000211

AC:

AN:

227126

AF XY:

0.000216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00365

Gnomad EAS exome

AF:

0.0000581

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000804

Gnomad OTH exome

AF:

0.000538

GnomAD4 exome

AF:

0.0000726

AC:

105

AN:

1445388

Hom.:

Cov.:

AF XY:

0.0000738

AC XY:

AN XY:

718008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33038

American (AMR)

AF:

0.00

AC:

AN:

43218

Ashkenazi Jewish (ASJ)

AF:

0.00278

AC:

AN:

25898

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39102

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

1103496

Other (OTH)

AF:

0.000218

AC:

AN:

59626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000660

AC:

AN:

151476

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41140

American (AMR)

AF:

0.00

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67884

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000672

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000184

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to (1)

Hypertrophic cardiomyopathy 14 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.48

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.1

PhyloP100

7.5

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.85

MutPred

0.67

Loss of ubiquitination at K1175 (P = 0.0098)

MVP

0.88

MPC

3.1

ClinPred

0.43

GERP RS

4.2

Varity_R

0.50

gMVP

0.79

Mutation Taster

=17/83

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over