14-23389062-AGGG-AGGGGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_002471.4(MYH6):c.3979-9_3979-8dupCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

MYH6
NM_002471.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.275

Publications

5 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):

hypertrophic cardiomyopathy 14
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
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: LIMITED Submitted by: ClinGen

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6

Variant 14-23389062-A-AGG is Benign according to our data. Variant chr14-23389062-A-AGG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 928727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.3979-9_3979-8dupCC		splice_region intron	N/A	NP_002462.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3979-8_3979-7insCC		splice_region intron	N/A	ENSP00000386041.3

Frequencies

GnomAD3 genomes

AF:

0.0000259

AC:

AN:

115624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000329

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000427

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1059776

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

528120

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30388

American (AMR)

AF:

0.0000338

AC:

AN:

29556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19388

East Asian (EAS)

AF:

0.0000360

AC:

AN:

27796

South Asian (SAS)

AF:

0.0000458

AC:

AN:

65522

European-Finnish (FIN)

AF:

0.0000286

AC:

AN:

35024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4192

European-Non Finnish (NFE)

AF:

0.0000212

AC:

AN:

802756

Other (OTH)

AF:

0.0000886

AC:

AN:

45154

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.290

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:

0.0000259

AC:

AN:

115624

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

56768

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

38780

American (AMR)

AF:

0.00

AC:

AN:

11278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2598

East Asian (EAS)

AF:

0.000329

AC:

AN:

3042

South Asian (SAS)

AF:

0.00

AC:

AN:

3432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.0000427

AC:

AN:

46892

Other (OTH)

AF:

0.00

AC:

AN:

1568

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 21, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYH6 c.3979-9_3979-8dupCC alters multiple nucleotides in a repeat Cs region located close to a canonical splice site. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 139674 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3979-9_3979-8dupCC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, several del/dup variants have been found in this region and classified as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

Hypertrophic cardiomyopathy 14

Benign:1

Jul 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.28

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over