NM_002471.4:c.3979-8dupC

Variant names:

• chr14-23389062-A-AG
• rs193922652
• NM_002471.4:c.3979-8dupC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002471.4(MYH6):​c.3979-8dupC variant causes a splice region, 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, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7 O:1
• 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-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: {Likely_benign=1, 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 rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.3979-8dupC		splice_region_variant, intron_variant	Intron 28 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-8_3979-7insC		splice_region_variant, intron_variant	Intron 28 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.00714 AC: 825 AN: 115566 Hom.: 5 Cov.: 0

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.: 0 AF XY: 0.00638 AC XY: 487 AN XY: 76278

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.: 0 Cov.: 0 AF XY: 0.00410 AC XY: 2159 AN XY: 526192

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.: 5 Cov.: 0 AF XY: 0.00753 AC XY: 428 AN XY: 56842

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:3 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4 Other:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Mar 15, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atrial septal defect Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 14 Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 13, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH6: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs193922652; hg19: chr14-23858271;