chr1-236762544-G-A

Position:

chr1-236762544-G-A

Variant summary

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

The NM_001103.4(ACTN2):c.2610G>A(p.Ser870Ser) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -7.44

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:

ACTN2 (HGNC:):

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ACTN2	NM_001103.4 linkuse as main transcript	c.2610G>A	p.Ser870Ser	synonymous_variant	21/21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 linkuse as main transcript	c.2610G>A	p.Ser870Ser	synonymous_variant	21/21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 linkuse as main transcript	n.2982G>A		non_coding_transcript_exon_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.2610G>A	p.Ser870Ser	synonymous_variant	21/21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.165

AC:

25065

AN:

151948

Hom.:

2193

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.153

AC XY:

111117

AN XY:

727212

show subpopulations

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.:

AF XY:

0.171

AC XY:

12710

AN XY:

74342

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dilated cardiomyopathy 1AA

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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