NM_002471.4:c.3979-8dupC

Variant summary

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

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7O: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]

Genome browser will be placed here

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: {Uncertain_significance=3, Benign=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
MYH6NM_002471.4 linkc.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
MYH6ENST00000405093.9 linkc.3979-8_3979-7insC splice_region_variant, intron_variant Intron 28 of 38 5 NM_002471.4 ENSP00000386041.3 P13533

Frequencies

GnomAD3 genomes
AF:
0.00714
AC:
825
AN:
115566
Hom.:
5
Cov.:
0
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.:
0
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.:
0
Cov.:
0
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.:
5
Cov.:
0
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:7Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:4Other:1
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria 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. -

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

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.

Other links and lift over

dbSNP: rs193922652; hg19: chr14-23858271; API