Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_001103.4(ACTN2):c.2181G>T(p.Leu727Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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 Likely benign (★★).
ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]
ACTN2 Gene-Disease associations (from GenCC):
intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
myopathy, congenital, with structured cores and z-line abnormalities
Our verdict: Benign. The variant received -11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
Variant 1-236757512-G-T is Benign according to our data. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236757512-G-T is described in CliVar as Likely_benign. Clinvar id is 238299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.353 with no splicing effect.
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -