rs121434590
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_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
Consequence
NM_002472.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYH8 | ENST00000403437.2 | c.2021G>A | p.Arg674Gln | missense_variant | Exon 18 of 40 | 5 | NM_002472.3 | ENSP00000384330.2 | ||
ENSG00000272736 | ENST00000399342.6 | n.206+647C>T | intron_variant | Intron 2 of 3 | 3 | |||||
ENSG00000272736 | ENST00000581304.1 | n.143+686C>T | intron_variant | Intron 2 of 3 | 3 | |||||
MYHAS | ENST00000587182.2 | n.155+686C>T | intron_variant | Intron 2 of 10 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727196
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74280
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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) -
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Hecht syndrome Pathogenic:2
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 -
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Carney complex - trismus - pseudocamptodactyly syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at