rs142142718

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001103.4(ACTN2):c.1714C>T(p.Arg572Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R572Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.07

Publications

3 publications found

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 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)

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 1-236751527-C-T is Benign according to our data. Variant chr1-236751527-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43914.

BS2

High AC in GnomAd4 at 17 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.1714C>T	p.Arg572Trp	missense_variant	Exon 15 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.1714C>T	p.Arg572Trp	missense_variant	Exon 15 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.2086C>T		non_coding_transcript_exon_variant	Exon 17 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.1714C>T	p.Arg572Trp	missense_variant	Exon 15 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251408

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33474

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111976

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41420

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 22, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Arg572Trp (c.1714C>T) in exon 15 of the ACTN2 gene (NM_001103.3) Chromosome position: 1:236914827 C / T Based on the information reviewed below, we classify this as a VUS (leaning toward VUS, Probably Benign), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It may be a benign rare variant more common among people with African ancestry such as our patient. The ExAC browserâ€™s â€œFiltering Allele Frequencyâ€ (Whiffin et al. 2017) suggests that this variant is too common to plausibly cause disease. This variant has previously been reported in 2 unrelated cases of cardiomyopathy in the literature. However, there is no published segregation data. The variant was first reported in an individual with dilated cardiomyopathy, or clinical features suggestive of dilated cardiomyopathy, who was tested at the Laboratory for Molecular Medicine (Pugh et al. 2014; PMID: 24503780 & 27532257). In ClinVar, LMM specifies that this proband had African ancestry. It was also identified in an individual affected with hypertrophic cardiomyopathy tested at the Oxford Medical Genetics Laboratories (Walsh et al. 2017 PMID: 27532257). No ethnicity information is provided for the HCM patient. Of note, when Walsh et al. compared variants in ACTN2 for HCM cases and ExAC â€œcontrolsâ€, they found no significant excess of rare genetic variation in the HCM cases, suggesting that there is not a solid causal connection between this gene and HCM. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 16 individuals in the gnomAD database, most of them with African ancestry like our patient. Specifically, the variant was observed in 13 individuals with African ancestry (for the highest allele frequency: 0.054%), 2 with Latino ancestry, and 1 with East Asian ancestry. There are also 3 individuals with a different variant at this location: p.Arg572Gln. gnomAD currently includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Sep 06, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individual of African-American descent with DCM, left bundle branch block, and a family history of DCM; also reported in another individual with HCM but detailed information is not provided (Pugh et al., 2014; Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780) -

not specified

Uncertain:1

Feb 10, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg572Trp v ariant has not been reported in the literature but has been identified in 1 Blac k DCM proband tested by our laboratory. Please note: we have only sequenced the ACTN2 in 45 Black individuals and healthy control information is unavailable fro m either public databases or scientific literature, such that the full spectrum of benign variation has not yet been defined for this population. Future analysi s could reveal that the Arg572Trp variant is common and therefore unlikely to be pathogenic. However, arginine (Arg) at position 572 is highly conserved across evolutionary distant species, increasing the likelihood that the change is patho genic. In addition, computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the variant may impact the protein although this information is not predict ive enough to assume pathogenicity. In summary, the clinical significance of th is variant cannot be determined without further studies. -

Cardiovascular phenotype

Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1714C>T (p.R572W) alteration is located in exon 15 (coding exon 15) of the ACTN2 gene. This alteration results from a C to T substitution at nucleotide position 1714, causing the arginine (R) at amino acid position 572 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

.;.;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.72

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.5

.;M;M

PhyloP100

1.1

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.17

.;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

1.0

.;.;D

Vest4

0.85

MVP

0.71

MPC

0.84

ClinPred

0.21

GERP RS

4.1

Varity_R

0.36

gMVP

0.80

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over