rs774780856

chr1-236751588-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001103.4(ACTN2):c.1775G>T(p.Arg592Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.31

Genes affected

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1775G>T	p.Arg592Ile	missense_variant	15/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.1775G>T	p.Arg592Ile	missense_variant	15/21
ACTN2	NR_184402.1	n.2147G>T		non_coding_transcript_exon_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1775G>T	p.Arg592Ile	missense_variant	15/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251404 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727176

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces arginine with isoleucine at codon 592 of the ACTN2 protein (p.Arg592Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is present in population databases (rs774780856, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 520511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 12, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The p.R592I variant (also known as c.1775G>T), located in coding exon 15 of the ACTN2 gene, results from a G to T substitution at nucleotide position 1775. The arginine at codon 592 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0011	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Benign	0.96
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.19
Sift4G	Benign	0.12	T;T;T
Polyphen		0.41	.;.;B
Vest4		0.64
MutPred		0.42		.;Gain of catalytic residue at S594 (P = 0.0216);Gain of catalytic residue at S594 (P = 0.0216);
MVP		0.64
MPC		0.58
ClinPred		0.81	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs774780856; hg19: chr1-236914888;