rs142482143

Positions:

chr1-236739318-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001103.4(ACTN2):c.893G>A(p.Arg298His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,613,850 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9

Conservation

PhyloP100: 8.14

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30664888).

BP6

Variant 1-236739318-G-A is Benign according to our data. Variant chr1-236739318-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43951.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=3}. Variant chr1-236739318-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000401 (61/151970) while in subpopulation NFE AF= 0.000794 (54/67972). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACTN2	NM_001103.4 linkuse as main transcript	c.893G>A	p.Arg298His	missense_variant	10/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2 linkuse as main transcript	c.893G>A	p.Arg298His	missense_variant	10/21		NP_001265272.1
ACTN2	NR_184402.1 linkuse as main transcript	n.1265G>A		non_coding_transcript_exon_variant	12/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.893G>A	p.Arg298His	missense_variant	10/21	1	NM_001103.4	ENSP00000355537	A1	P35609-1

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000453

AC:

114

AN:

251386

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000845

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000447

AC:

653

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000450

AC XY:

327

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000537

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000401

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000758

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000552

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 13, 2017	Given the weak case data and frequency in the general population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has was identified in one patient with HCM at our center. Testing was performed at Invitae. It has been seen elsewhere in one case of DCM and one case of LVNC. There is weak case data. Pugh et al. (2014) reports the variant was present in one case of DCM. Testing was done by LMM and, at that time. No other clinical data was available. In silico data are conflicting on predicted effect of this variant on protein function. The variant is present in 126 of 138,513 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 109 of 63,292 individuals of European descent (MAF = 0.086%). Of note, one of these individuals is homozygous for the variant. It has also been seen in 11 of 17,210 individuals of Latino descent (MAF = 0.03196%), 1 of 5076 Ashkenazi Jewish individual (MAF = 0.00985%), 2 of 15,391 individuals of South Asian descent, one of which is homozygous (MAF = 0.009746). It is also present at smaller frequencies in the Finnish and East Asian populations. The average coverage at that site in gnomAD is 90x. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ACTN2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	R298H variant in the ACTN2 gene has not been reported as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Although R298H results in a conservative amino acid substitution of one positively charged residue for another, the Arg298 position is conserved across species. In silico analysis predicts R298H is damaging to the protein structure/function. However, no mutations have been reported in association with cardiomyopathy in nearby residues. Furthermore, the NHLBI ESP Exome Variant Server reports R298H was observed in approximately 8/8,600 alleles (0.092%) from individuals of European background, indicating it is not a common benign variant in these populations. We interpret R298H as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Arg298His var iant in ACTN2 has been identified by our laboratory in 1 individual with LVNC, 1 with DCM, and 1 with HCM. However, at least one of these individuals carried an additional variant sufficient to explain disease. This variant has also been re ported in ClinVar (Variation ID: 43951). This variant has been identified in 0.1 % (61/66736) of European chromosomes, including 1 homozygote, by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142482143). Com putational prediction tools and conservation analysis suggest that the p.Arg298H is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, while the clinical significance of t he p.Arg298His variant is uncertain, its frequency suggests that it is more like ly to be benign. -

Dilated cardiomyopathy 1AA

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

ACTN2 NM_001103.3 exon 10 p.Arg298His (c.893G>A): This variant has been reported in the literature in one individual with DCM, one with HCM, and three with features of LVNC (Pugh 2014 PMID:24503780, Miszalski-Jamka 2017 PMID:28798025, Mademont-Soler 2017 PMID:28771489). However, at least two of these individuals also carried additional variants of uncertain clinical significance in other cardiomyopathy genes (Pugh 2014 PMID:24503780, Miszalski-Jamka 2017 PMID:28798025). This variant is present in 0.08% (110/126584) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-236902618-G-A), including one homozygote. This variant is present in ClinVar (Variation ID:43951). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 21, 2020

- -

ACTN2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

.;.;D

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.5

.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.1

.;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.013

.;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.84

.;.;P

Vest4

0.79

MVP

0.82

MPC

0.27

ClinPred

0.20

GERP RS

4.6

Varity_R

0.27

gMVP

0.44

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

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