rs142142718

chr1-236751527-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000112 (17/152122) while in subpopulation AFR AF= 0.000362 (15/41420). AF 95% confidence interval is 0.000222. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1714C>T	p.Arg572Trp	missense_variant	15/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.1714C>T	p.Arg572Trp	missense_variant	15/21
ACTN2	NR_184402.1	n.2086C>T		non_coding_transcript_exon_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1714C>T	p.Arg572Trp	missense_variant	15/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152122 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251408 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135886

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727212

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74296

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2022	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) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 22, 2017	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 browser’s “Filtering Allele Frequency” (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 “controls”, 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2011

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
REVEL	Uncertain	0.33
Sift4G	Benign	0.18	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.85
MVP		0.71
MPC		0.84
ClinPred		0.21	T
GERP RS		4.1
Varity_R		0.36
gMVP		0.80

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

Other links and lift over

dbSNP: rs142142718; hg19: chr1-236914827; COSMIC: COSV63975408; COSMIC: COSV63975408;