rs727505112
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001103.4(ACTN2):c.1899T>G(p.His633Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. H633R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1899T>G | p.His633Gln | missense_variant | 16/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.1899T>G | p.His633Gln | missense_variant | 16/21 | ||
ACTN2 | NR_184402.1 | n.2271T>G | non_coding_transcript_exon_variant | 18/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1899T>G | p.His633Gln | missense_variant | 16/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251324Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461844Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9AN XY: 727222
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 18, 2014 | Variant classified as Uncertain Significance - Favor Benign. The His633Gln varia nt in ACTN2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that the His633Gln variant may not impact the protein, and seve ral reptile and fish species carry a glutamine (Gln) at this position suggesting that this change may be tolerated. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the His633Gln variant is uncertain, the presence of the variant amino acid in o ther species suggests that it is more likely to be benign. - |
Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 01, 2021 | The p.H633Q variant (also known as c.1899T>G), located in coding exon 16 of the ACTN2 gene, results from a T to G substitution at nucleotide position 1899. The histidine at codon 633 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. 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. - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at