rs121434590
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Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_002472.3(MYH8):c.2021G>A(p.Arg674Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MYH8
NM_002472.3 missense
NM_002472.3 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 7.78
Genes affected
MYH8 (HGNC:7578): (myosin heavy chain 8) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH8. . Gene score misZ 0.34953 (greater than the threshold 3.09). Trascript score misZ 3.2125 (greater than threshold 3.09). GenCC has associacion of gene with trismus-pseudocamptodactyly syndrome, Carney complex - trismus - pseudocamptodactyly syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 17-10406924-C-T is Pathogenic according to our data. Variant chr17-10406924-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10406924-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH8 | NM_002472.3 | c.2021G>A | p.Arg674Gln | missense_variant | 18/40 | ENST00000403437.2 | NP_002463.2 | |
MYHAS | NR_125367.1 | n.167+686C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH8 | ENST00000403437.2 | c.2021G>A | p.Arg674Gln | missense_variant | 18/40 | 5 | NM_002472.3 | ENSP00000384330.2 | ||
ENSG00000272736 | ENST00000399342.6 | n.206+647C>T | intron_variant | 3 | ||||||
ENSG00000272736 | ENST00000581304.1 | n.143+686C>T | intron_variant | 3 | ||||||
MYHAS | ENST00000587182.2 | n.155+686C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727196
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74280
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2024 | Segregates with disease in many affected individuals from several families in published literature (PMID: 15282353, 17041932); Reported previously as a maternally inherited pathogenic variant in a patient with trismus-pseudocamptodactyly syndrome who also harbored a de novo pathogenic variant in a different gene consistent with a second disorder. It was thought that the combination of these two variants contributed to the more involved phenotype observed in this patient (PMID: 34321323); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17041932, 15282353, 18049072, 28377322, 20949528, 33109698, 31630644, 34321323, 35982159) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 31, 2016 | - - |
Hecht syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated actin-binding region of the myosin motor domain (UniProt). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in more than ten unrelated individuals with trismus-pseudocamptodactyly syndrome (MIM#158300) (ClinVar, HGMD, LOVD, PMIDs: 15282353, 17041932, 18049072, 20949528). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregate in affected individuals in several multigenerational families (PMIDs: 15282353, 17041932). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2010 | - - |
Carney complex - trismus - pseudocamptodactyly syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2010 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0797);
MVP
MPC
ClinPred
D
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gMVP
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at