rs35956798

chr1-236744666-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.1296G>A(p.Ala432=) 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (280 hom., cov: 32)
  • Exomes 𝑓: 0.014 (374 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.70

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=-0.87).
• 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/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1296G>A	p.Ala432=	synonymous_variant	12/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.1296G>A	p.Ala432=	synonymous_variant	12/21
ACTN2	NR_184402.1	n.1668G>A		non_coding_transcript_exon_variant	14/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1296G>A	p.Ala432=	synonymous_variant	12/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6198 AN: 152208 Hom.: 279 Cov.: 32

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

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.: 32 AF XY: 0.0136 AC XY: 9855 AN XY: 727238

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.: 32 AF XY: 0.0408 AC XY: 3039 AN XY: 74496

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.: 65

Bravo AF: 0.0461

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Dec 04, 2008	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	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

- -

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

Jul 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	-0.87
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

Other links and lift over

dbSNP: rs35956798; hg19: chr1-236907966; COSMIC: COSV63973941; COSMIC: COSV63973941;