rs368451573
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_002471.4(MYH6):c.3604G>A(p.Val1202Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,607,176 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 0.00014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
MYH6
NM_002471.4 missense
NM_002471.4 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 1.56
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 Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MYH6
BP4
?
Computational evidence support a benign effect (MetaRNN=0.076346874).
BS2
?
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3604G>A | p.Val1202Met | missense_variant | 26/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3604G>A | p.Val1202Met | missense_variant | 26/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 151746Hom.: 0 Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000163 AC: 40AN: 245788Hom.: 0 AF XY: 0.000210 AC XY: 28AN XY: 133490
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GnomAD4 exome AF: 0.000102 AC: 149AN: 1455314Hom.: 0 Cov.: 34 AF XY: 0.000127 AC XY: 92AN XY: 723318
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 151862Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15AN XY: 74222
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 05, 2017 | The p.Val1202Met variant (rs368451573) has not been reported in the medical literature or gene specific variation databases but has been reported to ClinVar (Variation ID:312860) This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.03 percent (identified on 4 out of 12,956 chromosomes) and is listed in the genome Aggregation Database with an overall population frequency of 0.017 percent (identified on 47 out of 272,478 chromosomes). The valine at position 1202 is highly conserved, up to Opossum (considering 5 species, Alamut v.2.9.0) and computational analyses of the effects of the p.Val1202Met variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Val1202Met variant with certainty. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
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 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2023 | The p.V1202M variant (also known as c.3604G>A), located in coding exon 24 of the MYH6 gene, results from a G to A substitution at nucleotide position 3604. The valine at codon 1202 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in an individual with hypertrophic cardiomyopathy who also had variants in other cardiac-related genes, including a splice site mutation in MYBPC3 (Forleo C et al. PLoS ONE, 2017 Jul;12:e0181842). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is well conserved in available vertebrate species; however, methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypertrophic cardiomyopathy 14 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
T;T
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at