rs12063382

chr1-236762544-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001103.4(ACTN2):c.2610G>A(p.Ser870=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,890 control chromosomes in the GnomAD database, including 19,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2198 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17638 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -7.44

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-236762544-G-A is Benign according to our data. Variant chr1-236762544-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236762544-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.2610G>A	p.Ser870=	synonymous_variant	21/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.2610G>A	p.Ser870=	synonymous_variant	21/21
ACTN2	NR_184402.1	n.2982G>A		non_coding_transcript_exon_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.2610G>A	p.Ser870=	synonymous_variant	21/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25065 AN: 151948 Hom.: 2193 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.168 AC: 42246 AN: 251150 Hom.: 3839 AF XY: 0.167 AC XY: 22644 AN XY: 135774

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.152 AC: 222144 AN: 1461824 Hom.: 17638 Cov.: 33 AF XY: 0.153 AC XY: 111117 AN XY: 727212

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.0826

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.165 AC: 25101 AN: 152066 Hom.: 2198 Cov.: 32 AF XY: 0.171 AC XY: 12710 AN XY: 74342

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.0917

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.161

Alfa AF: 0.142 Hom.: 2467

Bravo AF: 0.161

Asia WGS AF: 0.186 AC: 647 AN: 3478

EpiCase AF: 0.145

EpiControl AF: 0.143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2009	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1AA Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2015

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	-0.84
Cadd	Benign	0.27
Dann	Benign	0.92

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: rs12063382; hg19: chr1-236925844; COSMIC: COSV63973348;