NM_001103.4:c.2485G>T

Variant names:

• chr1-236761132-G-T
• rs770335717
• NM_001103.4:c.2485G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001103.4(ACTN2):​c.2485G>T​(p.Glu829*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTN2 NM_001103.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.97
• Publications: 1 publications found

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 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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1AA

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• myopathy, distal, 6, adult-onset, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0745 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-236761132-G-T is Pathogenic according to our data. Variant chr1-236761132-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520508.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.2485G>T	p.Glu829*	stop_gained	Exon 20 of 21	NP_001094.1
	ACTN2	NM_001278343.2		c.2485G>T	p.Glu829*	stop_gained	Exon 20 of 21	NP_001265272.1
	ACTN2	NR_184402.1		n.2857G>T		non_coding_transcript_exon	Exon 22 of 23

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.2485G>T	p.Glu829*	stop_gained	Exon 20 of 21	ENSP00000355537.4
	ACTN2	ENST00000542672.7	TSL:1	c.2485G>T	p.Glu829*	stop_gained	Exon 20 of 21	ENSP00000443495.1
	ACTN2	ENST00000682015.1		c.2392G>T	p.Glu798*	stop_gained	Exon 19 of 20	ENSP00000506961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Nov 16, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu829*) in the ACTN2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the ACTN2 protein. This variant is not present in population databases (gnomAD no frequency). 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: 520508). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Cardiovascular phenotype Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E829* variant (also known as c.2485G>T), located in coding exon 20 of the ACTN2 gene, results from a G to T substitution at nucleotide position 2485. This changes the amino acid from a glutamic acid to a stop codon within coding exon 20. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (Ambry internal data). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of ACTN2, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 66 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.79
GERP RS		5.9
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs770335717; hg19: chr1-236924432; COSMIC: COSV63975464;