rs777744290

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001103.4(ACTN2):c.2194G>A(p.Ala732Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A732A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 9.96

Variant links:

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]

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACTN2	NM_001103.4 linkuse as main transcript	c.2194G>A	p.Ala732Thr	missense_variant	18/21	ENST00000366578.6
ACTN2	NM_001278343.2 linkuse as main transcript	c.2194G>A	p.Ala732Thr	missense_variant	18/21
ACTN2	NR_184402.1 linkuse as main transcript	n.2566G>A		non_coding_transcript_exon_variant	20/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.2194G>A	p.Ala732Thr	missense_variant	18/21	1	NM_001103.4	A1	P35609-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251492

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135918

show subpopulations

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:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 03, 2015

The p.Ala732Thr variant in ACTN2 has been identified by our laboratory in 2 indi viduals: 1 with HCM and 1 DCM. However, both individuals carried an additional v ariant of likely clinical significance (Zimmerman 2010, LMM unpublished data). The p.Ala732Thr variant has also been identified in 5/66736 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ala7 32Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala732Thr variant is uncertain. -

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

Oct 13, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2018

The Ala732Thr variant in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala732Thr results in a non-conservative amino acid substitution of a nonpolar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala732Thr is damaging to the protein structure/function. The Ala732Thr variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with DCM. With the clinical and molecular information available at this time, we cannot definitively determine if Ala732Thr are disease-causing mutations or rare benign variants. The variant is found in DCM panel(s). -

Myopathy, distal, 6, adult-onset, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Sep 29, 2023

The heterozygous p.Ala732Thr variant in ACTN2 was identified by the Broad Institute Rare Genomes Project in 4 family members with distal myopathy and/or cardiomyopathy (publication in progress). However, this family carries another ACTN2 variant in cis (p.Asp841fs, ClinVar Variation ID: 201652) that is more likely to explain their disease. The p.Ala732Thr variant has also been reported in 2 individuals with cardiomyopathy (PMID: 20474083, 32826072), and has been identified in 0.007% (8/113766) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP {rs777744290}). This variant has been seen in the general population, in a heterozygous state, at greater rate than expected for disorder. This variant has also been reported in ClinVar (Variation ID: 201647) and has been interpreted as a variant of uncertain significance by GeneDx, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine}, Ambry Genetics, and Fulgent Genetics and as likely benign by Invitae. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ala732Thr variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_supporting, BP2, PP1 (Richards 2015). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2024

The p.A732T variant (also known as c.2194G>A), located in coding exon 18 of the ACTN2 gene, results from a G to A substitution at nucleotide position 2194. The alanine at codon 732 is replaced by threonine, an amino acid with similar properties. This variant was first detected in conjunction with another ACTN2 alteration in an individual with dilated cardiomyopathy (DCM); however, the phase of these alterations was unknown (Zimmerman et al. Genet. Med. 2010;12(5):268-78). Additionally, this alteration has been reported in a DCM cohort (Peña-Peña ML et al. Med Clin (Barc), 2021 May;156:485-495). 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. -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.0049

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.6

.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.3

.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.17

.;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

1.0

.;.;D

Vest4

0.84

MutPred

0.59

.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);

MVP

0.66

MPC

0.81

ClinPred

0.56

GERP RS

5.7

Varity_R

0.44

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over