rs142943120

Positions:

• chr1-236747686-G-A
• chr1-236747686-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001103.4(ACTN2):​c.1426G>A​(p.Ala476Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000279 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A476S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 5.80

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010438591).
• BP6: Variant 1-236747686-G-A is Benign according to our data. Variant chr1-236747686-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192111.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=6, Uncertain_significance=1}. Variant chr1-236747686-G-A is described in Lovd as [Benign]. Variant chr1-236747686-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00141 (214/152236) while in subpopulation AFR AF= 0.00484 (201/41528). AF 95% confidence interval is 0.00429. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1426G>A	p.Ala476Thr	missense_variant	13/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.1426G>A	p.Ala476Thr	missense_variant	13/21
ACTN2	NR_184402.1	n.1798G>A		non_coding_transcript_exon_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1426G>A	p.Ala476Thr	missense_variant	13/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251388 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135876

Gnomad AFR exome AF: 0.00548

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105 AN XY: 727162

Gnomad4 AFR exome AF: 0.00550

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74430

Gnomad4 AFR AF: 0.00484

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000464 Hom.: 0

Bravo AF: 0.00172

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	ACTN2: BS1, BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 27, 2017	p.Ala476Thr in exon 13 of ACTN2: This variant is not expected to have clinical s ignificance because it has been identified in 0.53% (128/24020) of African chrom osomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs142943120). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 19, 2018	Variant summary: ACTN2 c.1426G>A (p.Ala476Thr) results in a non-conservative amino acid change located in one of the Spectrin repeats (IPR002017) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 277184 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0053 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 210 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1426G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (2x), likely benign (3x), benign (1x)). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dilated cardiomyopathy 1AA Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 28, 2016

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 17, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2018

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	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.93	.;.;P
Vest4		0.56
MVP		0.49
MPC		0.59
ClinPred		0.033	T
GERP RS		5.7
Varity_R		0.28
gMVP		0.21

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: rs142943120; hg19: chr1-236910986;