rs727504399

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_005159.5(ACTC1):​c.76G>A​(p.Asp26Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACTC1
NM_005159.5 missense

Scores

10
6
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 6.12
Variant links:
Genes affected
ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]
GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ACTC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 4.5244 (above the threshold of 3.09). Trascript score misZ: 6.3156 (above the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy, hypertrophic cardiomyopathy, atrial septal defect 5, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.812
PP5
Variant 15-34794733-C-T is Pathogenic according to our data. Variant chr15-34794733-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177917.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTC1NM_005159.5 linkc.76G>A p.Asp26Asn missense_variant Exon 2 of 7 ENST00000290378.6 NP_005150.1 P68032B3KPP5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTC1ENST00000290378.6 linkc.76G>A p.Asp26Asn missense_variant Exon 2 of 7 1 NM_005159.5 ENSP00000290378.4 P68032
ACTC1ENST00000560563.2 linkn.182G>A non_coding_transcript_exon_variant Exon 2 of 6 2
GJD2-DTENST00000503496.6 linkn.300-15763C>T intron_variant Intron 2 of 2 2
GJD2-DTENST00000671663.1 linkn.95-15763C>T intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461138
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726892
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Pathogenic:1
Oct 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 26 of the ACTC1 protein (p.Asp26Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ACTC1-related conditions and hypertrophic cardiomyopathy (PMID: 27532257, 30600190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177917). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 11 Pathogenic:1
Aug 02, 2024
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.76G>A (p.Asp26Asn) ACTC1 variant has been reported in our laboratory in a 67-year-old patient with diagnosis of hypertrophic cardiomyopathy. Father (sudden death 30y) and paternal grandmother (sudden death 50y). In our Hospital, it has been reported in another family with hypertrophic cardiomyopathy with positive segregation. This variant is present in population databases (gnomAD allele frequency 0.0000006198). This variant has been previously reported in a patients with hypertrophic cardiomyopathy [PMID 27532257, 30600190]. ClinVar contains an entry for this variant (Variation ID: 117917). In silico analysis (CADD, Revel) supports that this missense variant has a deleterious effect on protein structure/function. In summary, c.76G>A (p.Asp26Asn) ACTC1 variant meets our criteria to be classified as pathogenic based upon its absence from controls, computational evidence of pathogenicity in this family and having been widely described in relation to the patient´s phenotype. -

not specified Uncertain:1
Feb 11, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided Uncertain:1
Jul 11, 2018
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Asp26Asn (GAT>AAT):c.76 G>A in exon 2 of the ACTC1 gene (NM_005159.4). The Asp26Asn variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp26Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid residue with a neutral, polar Asparagine residue at a position that is conserved across species. In silico analysis predicts Asp26Asn is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Asp26Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in surrounding residues of the ACTC1 gene have been reported in association with HCM, suggesting this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Asp26Asn is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Uncertain
0.46
BayesDel_addAF
Uncertain
0.087
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-2.1
N
REVEL
Pathogenic
0.74
Sift4G
Uncertain
0.023
D
Polyphen
0.95
P
Vest4
0.43
MutPred
0.62
Loss of disorder (P = 0.1505);
MVP
0.92
MPC
1.7
ClinPred
0.98
D
GERP RS
4.2
Varity_R
0.84
gMVP
0.93

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.

Other links and lift over

dbSNP: rs727504399; hg19: chr15-35086934; COSMIC: COSV51757846; COSMIC: COSV51757846; API