rs370158816
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_002471.4(MYH6):c.898+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,612,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
MYH6
NM_002471.4 splice_donor_region, intron
NM_002471.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00003611
1
Clinical Significance
Conservation
PhyloP100: 0.187
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 14-23403342-G-A is Benign according to our data. Variant chr14-23403342-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407144.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.898+6C>T | splice_donor_region_variant, intron_variant | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.898+6C>T | splice_donor_region_variant, intron_variant | 5 | NM_002471.4 | P1 | |||
MYH6 | ENST00000557461.2 | n.965+6C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152130Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251468Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460142Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 726544
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74426
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | This variant has not been reported in the literature in individuals affected with MYH6-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 407144). This variant is present in population databases (rs370158816, gnomAD 0.05%). This sequence change falls in intron 10 of the MYH6 gene. It does not directly change the encoded amino acid sequence of the MYH6 protein. It affects a nucleotide within the consensus splice site. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 31, 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 20, 2020 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at