NM_001103.4:c.1892G>A
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2
The NM_001103.4(ACTN2):c.1892G>A(p.Arg631His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,052 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. R631C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
Publications
- intrinsic cardiomyopathyInheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
- myopathy, congenital, with structured cores and z-line abnormalitiesInheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathy 1AAInheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- heart conduction diseaseInheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
- myopathy, distal, 6, adult-onset, autosomal dominantInheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1892G>A | p.Arg631His | missense_variant | Exon 16 of 21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.1892G>A | p.Arg631His | missense_variant | Exon 16 of 21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.2264G>A | non_coding_transcript_exon_variant | Exon 18 of 23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000398 AC: 10AN: 251314 AF XY: 0.0000515 show subpopulations
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461836Hom.: 0 Cov.: 36 AF XY: 0.0000385 AC XY: 28AN XY: 727220 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74374 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
The p.R631H variant (also known as c.1892G>A), located in coding exon 16 of the ACTN2 gene, results from a G to A substitution at nucleotide position 1892. The arginine at codon 631 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Cardiomyopathy Benign:1
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Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at