1-236747720-G-T

Variant names:

• chr1-236747720-G-T
• rs727504619
• NM_001103.4:c.1460G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001103.4(ACTN2):​c.1460G>T​(p.Cys487Phe) variant causes a missense 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C487R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.95
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-236747719-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 694348.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.1460G>T	p.Cys487Phe	missense_variant	Exon 13 of 21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.1460G>T	p.Cys487Phe	missense_variant	Exon 13 of 21		NP_001265272.1
ACTN2	NR_184402.1	n.1832G>T		non_coding_transcript_exon_variant	Exon 15 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.1460G>T	p.Cys487Phe	missense_variant	Exon 13 of 21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Cys487Phe variant in ACTN2 has not been reported in individuals with cardiom yopathy or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that th is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant. -

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

Apr 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTN2 protein function. ClinVar contains an entry for this variant (Variation ID: 179093). This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 487 of the ACTN2 protein (p.Cys487Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.2	.;M;M
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.1	.;D;D
REVEL	Uncertain	0.63
Sift	Benign	0.065	.;T;T
Sift4G	Pathogenic	0.0010	D;T;T
Polyphen		0.99	.;.;D
Vest4		0.89
MutPred		0.48		.;Gain of MoRF binding (P = 0.0741);Gain of MoRF binding (P = 0.0741);
MVP		0.85
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.65
Mutation Taster		=207/93	polymorphism

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

Other links and lift over

dbSNP: rs727504619; hg19: chr1-236911020;