rs377716628
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_002471.4(MYH6):c.3230A>T(p.Gln1077Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1077R) has been classified as Uncertain significance.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3230A>T | p.Gln1077Leu | missense_variant | 24/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3230A>T | p.Gln1077Leu | missense_variant | 24/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000282 AC: 43AN: 152240Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251454Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135900
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461822Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 727218
GnomAD4 genome ? AF: 0.000282 AC: 43AN: 152358Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74508
ClinVar
Submissions by phenotype
Atrial septal defect 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 07, 2022 | This MYH6 variant (rs377716628) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African/African American subpopulation (gnomAD: 32/24972 alleles; 0.13%, no homozygotes). This patient's ethnicity is reported to be Brazilian. This variant has been previously reported to ClinVar. Two bioinformatic tools queried predict that this substitution would be damaging, and the glutamine residue at this position is strongly conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 24 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.3230A>T (p.Gln1077Leu) to be uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 11, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Hypertrophic cardiomyopathy 14 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at