rs35956798

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001103.4(ACTN2):c.1296G>A(p.Ala432Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,614,194 control chromosomes in the GnomAD database, including 654 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. A432A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.041 ( 280 hom., cov: 32)

Exomes 𝑓: 0.014 ( 374 hom. )

Consequence

ACTN2
NM_001103.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.70

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-236744666-G-A is Benign according to our data. Variant chr1-236744666-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236744666-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.1296G>A	p.Ala432Ala	synonymous_variant	Exon 12 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.1296G>A	p.Ala432Ala	synonymous_variant	Exon 12 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.1668G>A		non_coding_transcript_exon_variant	Exon 14 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.1296G>A	p.Ala432Ala	synonymous_variant	Exon 12 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6198

AN:

152208

Hom.:

279

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0354

GnomAD3 exomes

AF:

0.0157

AC:

3954

AN:

251274

Hom.:

122

AF XY:

0.0137

AC XY:

1864

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00343

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0142

AC:

20692

AN:

1461868

Hom.:

374

Cov.:

AF XY:

0.0136

AC XY:

9855

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00357

Gnomad4 FIN exome

AF:

0.00380

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0408

AC:

6213

AN:

152326

Hom.:

280

Cov.:

AF XY:

0.0408

AC XY:

3039

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.117

Gnomad4 AMR

AF:

0.0202

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00490

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.0351

Alfa

AF:

0.0248

Hom.:

Bravo

AF:

0.0461

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 04, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 25, 2012

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 15, 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

-0.87

CADD

Benign

0.077

DANN

Benign

0.63

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

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