chr14-23389062-AG-A

Position:

• chr14-23389062-AG-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_002471.4(MYH6):​c.3979-8del 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 0.35 (8254 hom., cov: 0)
  • Exomes 𝑓: 0.31 (26611 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8 O:2
• Conservation: PhyloP100: 0.275

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 14-23389062-AG-A is Benign according to our data. Variant chr14-23389062-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=2, Benign=4, Uncertain_significance=3}. Variant chr14-23389062-AG-A is described in Lovd as [Benign]. Variant chr14-23389062-AG-A is described in Lovd as [Benign]. Variant chr14-23389062-AG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4	c.3979-8del		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	c.3979-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 40782 AN: 115534 Hom.: 8236 Cov.: 0

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.260

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.320 AC: 44689 AN: 139674 Hom.: 4831 AF XY: 0.320 AC XY: 24389 AN XY: 76278

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.288

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.308 AC: 297903 AN: 966060 Hom.: 26611 Cov.: 0 AF XY: 0.307 AC XY: 147489 AN XY: 479754

Gnomad4 AFR exome AF: 0.616

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.323

GnomAD4 genome AF: 0.353 AC: 40854 AN: 115646 Hom.: 8254 Cov.: 0 AF XY: 0.345 AC XY: 19621 AN XY: 56834

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.337

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 04, 2016	- -

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

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 2 Other:1

not provided, no classification provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

-

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs193922652; hg19: chr14-23858271;