rs116464082

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001103.4(ACTN2):c.870G>A(p.Ala290Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,589,584 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 7 hom., cov: 28)

Exomes 𝑓: 0.00056 ( 7 hom. )

Consequence

ACTN2
NM_001103.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0190

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 1-236737208-G-A is Benign according to our data. Variant chr1-236737208-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236737208-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.019 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00469 (701/149370) while in subpopulation AFR AF= 0.0161 (661/41066). AF 95% confidence interval is 0.0151. There are 7 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High AC in GnomAd4 at 701 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.870G>A	p.Ala290Ala	synonymous_variant	Exon 9 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.870G>A	p.Ala290Ala	synonymous_variant	Exon 9 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.1242G>A		non_coding_transcript_exon_variant	Exon 11 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.870G>A	p.Ala290Ala	synonymous_variant	Exon 9 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.00469

AC:

700

AN:

149250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00142

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.000216

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00398

GnomAD3 exomes

AF:

0.00129

AC:

324

AN:

251296

Hom.:

AF XY:

0.00104

AC XY:

141

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000562

AC:

809

AN:

1440214

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

376

AN XY:

716450

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.000928

Gnomad4 ASJ exome

AF:

0.000197

Gnomad4 EAS exome

AF:

0.0000773

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00469

AC:

701

AN:

149370

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

315

AN XY:

72720

show subpopulations

Gnomad4 AFR

AF:

0.0161

Gnomad4 AMR

AF:

0.00142

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000391

Gnomad4 SAS

AF:

0.000216

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00393

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00471

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

May 07, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 06, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala290Ala in exon 9 of ACTN2: This variant is classified as benign because it do es not change the amino acid and is frequent in the general population (rs116464 082, NHLBI Exome Sequencing Project; MAF >1%). -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 29, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACTN2 c.870G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 251296 control chromosomes, predominantly at a frequency of 0.017 within the African or African-American subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 680 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 or African-American origin. To our knowledge, no occurrence of c.870G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiomyopathy

Benign:1

Sep 16, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1AA

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype

Benign:1

Aug 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.4

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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