Variant 14-23389062-AGGG-AGGGG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002471.4(MYH6):c.3979-8_3979-7insC variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0071 ( 5 hom., cov: 0)

Exomes 𝑓: 0.0037 ( 0 hom. )

Consequence

MYH6
NM_002471.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6O:1

Conservation

PhyloP100: 0.275

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 14-23389062-A-AG is Benign according to our data. Variant chr14-23389062-A-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179575.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=3, not_provided=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00713 (825/115680) while in subpopulation SAS AF= 0.0216 (74/3430). AF 95% confidence interval is 0.0176. There are 5 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 825 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.3979-8_3979-7insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.3979-8_3979-7insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes

AF:

0.00714

AC:

825

AN:

115566

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00740

Gnomad AMR

AF:

0.00941

Gnomad ASJ

AF:

0.00965

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0219

Gnomad FIN

AF:

0.00578

Gnomad MID

AF:

0.0310

Gnomad NFE

AF:

0.00962

Gnomad OTH

AF:

0.0121

GnomAD3 exomes

AF:

0.00589

AC:

822

AN:

139674

Hom.:

AF XY:

0.00638

AC XY:

487

AN XY:

76278

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.00865

Gnomad SAS exome

AF:

0.0139

Gnomad FIN exome

AF:

0.00344

Gnomad NFE exome

AF:

0.00507

Gnomad OTH exome

AF:

0.00585

GnomAD4 exome

AF:

0.00367

AC:

3873

AN:

1056040

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2159

AN XY:

526192

show subpopulations

Gnomad4 AFR exome

AF:

0.000395

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00425

Gnomad4 EAS exome

AF:

0.00700

Gnomad4 SAS exome

AF:

0.0113

Gnomad4 FIN exome

AF:

0.00750

Gnomad4 NFE exome

AF:

0.00277

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.00713

AC:

825

AN:

115680

Hom.:

Cov.:

AF XY:

0.00753

AC XY:

428

AN XY:

56842

show subpopulations

Gnomad4 AFR

AF:

0.00129

Gnomad4 AMR

AF:

0.00940

Gnomad4 ASJ

AF:

0.00965

Gnomad4 EAS

AF:

0.0148

Gnomad4 SAS

AF:

0.0216

Gnomad4 FIN

AF:

0.00578

Gnomad4 NFE

AF:

0.00964

Gnomad4 OTH

AF:

0.0119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 26, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2021	Variant summary: MYH6 c.3979-8dupC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0059 in 139674 control chromosomes. The observed variant frequency is approximately 235 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3979-8dupC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Dilated Cardiomyopathy, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Atrial septal defect

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over