14-23386302-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002471.4(MYH6):c.4959+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,092 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 2 hom., cov: 31)

Exomes 𝑓: 0.011 ( 113 hom. )

Consequence

MYH6
NM_002471.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -4.55

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 14-23386302-C-T is Benign according to our data. Variant chr14-23386302-C-T is described in ClinVar as Benign. ClinVar VariationId is 36631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00744 (1134/152322) while in subpopulation NFE AF = 0.0114 (775/68016). AF 95% confidence interval is 0.0107. There are 2 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1134 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.4959+13G>A		intron	N/A	NP_002462.2	P13533

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYH6	ENST00000405093.9	TSL:5 MANE Select	c.4959+13G>A	intron	N/A	ENSP00000386041.3	P13533
MYH6	ENST00000968262.1		c.4992+13G>A	intron	N/A	ENSP00000638321.1
MYH6	ENST00000968257.1		c.4959+13G>A	intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes

AF:

0.00746

AC:

1136

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00857

AC:

2149

AN:

250798

AF XY:

0.00888

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0112

AC:

16342

AN:

1461770

Hom.:

113

Cov.:

AF XY:

0.0109

AC XY:

7910

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33476

American (AMR)

AF:

0.00228

AC:

102

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00735

AC:

634

AN:

86246

European-Finnish (FIN)

AF:

0.0172

AC:

919

AN:

53404

Middle Eastern (MID)

AF:

0.00386

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0125

AC:

13937

AN:

1112000

Other (OTH)

AF:

0.00939

AC:

567

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1057

2115

3172

4230

5287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.00744

AC:

1134

AN:

152322

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

528

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00286

AC:

119

AN:

41574

American (AMR)

AF:

0.00281

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00684

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

775

AN:

68016

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0100

Hom.:

Bravo

AF:

0.00685

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Cardiomyopathy (2)

not provided (2)

Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.073

(source)

DANN

Benign

0.65

PhyloP100

-4.6

Mutation Taster

=100/0

polymorphism

(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

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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