rs80257412

Positions:

• chr1-236747683-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001103.4(ACTN2):​c.1423G>A​(p.Asp475Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,920 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D475D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (163 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 9.96

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002451241).
• BP6: Variant 1-236747683-G-A is Benign according to our data. Variant chr1-236747683-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236747683-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1423G>A	p.Asp475Asn	missense_variant	13/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.1423G>A	p.Asp475Asn	missense_variant	13/21
ACTN2	NR_184402.1	n.1795G>A		non_coding_transcript_exon_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1423G>A	p.Asp475Asn	missense_variant	13/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152116 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0924

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00778 AC: 1956 AN: 251376 Hom.: 97 AF XY: 0.00745 AC XY: 1012 AN XY: 135876

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0952

Gnomad SAS exome AF: 0.00487

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00273 AC: 3995 AN: 1461686 Hom.: 163 Cov.: 31 AF XY: 0.00275 AC XY: 1999 AN XY: 727162

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0774

Gnomad4 SAS exome AF: 0.00487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00709

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152234 Hom.: 24 Cov.: 32 AF XY: 0.00408 AC XY: 304 AN XY: 74438

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0920

Gnomad4 SAS AF: 0.00852

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.00375

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00711 AC: 863

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 19, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2013	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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2016	Variant summary: The ACTN2 c.1423G>A (p.Asp475Asn) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 861/119100 control chromosomes (including 45 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.090941 (777/8544). This frequency is about 3638 times the estimated maximal expected allele frequency of a pathogenic ACTN2 variant (0.000025), strong evidence that this is a common benign polymorphism found primarily in the populations of East Asian. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. This variant has also been found in patients with HCM, however, in one patient from a family another variant (TNNI3 p.Arg145Gly) was found to explain the phenotype (Zhao_2015). Taken together, this variant is classified as Benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 22, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Dilated cardiomyopathy 1AA Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 24, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2016

This alteration is classified as 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	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
Sift4G	Benign	0.16	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.69
MVP		0.75
MPC		0.65
ClinPred		0.053	T
GERP RS		5.7
Varity_R		0.33
gMVP		0.58

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: rs80257412; hg19: chr1-236910983; COSMIC: COSV63975220; COSMIC: COSV63975220;