chr1-236735642-G-C

Position:

chr1-236735642-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The ENST00000366578.6(ACTN2):c.705G>C(p.Val235=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,613,988 control chromosomes in the GnomAD database, including 346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V235V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0089 ( 47 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 299 hom. )

Consequence

ACTN2
ENST00000366578.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.46

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 1-236735642-G-C is Benign according to our data. Variant chr1-236735642-G-C is described in ClinVar as [Benign]. Clinvar id is 43943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735642-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0997 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACTN2	NM_001103.4 linkuse as main transcript	c.705G>C	p.Val235=	synonymous_variant	8/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2 linkuse as main transcript	c.783+1124G>C		intron_variant			NP_001265272.1
ACTN2	NR_184402.1 linkuse as main transcript	n.966G>C		non_coding_transcript_exon_variant	9/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.705G>C	p.Val235=	synonymous_variant	8/21	1	NM_001103.4	ENSP00000355537	A1	P35609-1

Frequencies

GnomAD3 genomes

AF:

0.00893

AC:

1357

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0521

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.0153

AC:

3840

AN:

251372

Hom.:

177

AF XY:

0.0149

AC XY:

2024

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.115

Gnomad SAS exome

AF:

0.00938

Gnomad FIN exome

AF:

0.0555

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.00550

AC:

8034

AN:

1461840

Hom.:

299

Cov.:

AF XY:

0.00560

AC XY:

4070

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0856

Gnomad4 SAS exome

AF:

0.00894

Gnomad4 FIN exome

AF:

0.0521

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.00889

AC:

1353

AN:

152148

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

857

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.107

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.0521

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00270

Hom.:

Bravo

AF:

0.00520

Asia WGS

AF:

0.0680

AC:

235

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2009	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2016	Variant summary: The ACTN2 c.705G>C (p.Val235Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool (MutationTaster) predicts a polymorphism outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1636/120960 control chromosomes (including 73 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.1080705 (932/8624). This frequency is about 4323 times the estimated maximal expected allele frequency of a pathogenic ACTN2 variant (0.000025), suggesting this is a common benign polymorphism found primarily in the populations of East Asian origin. This polymorphism has also been reported in HCM patients without strong evidence of causality. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 18, 2015

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Dilated cardiomyopathy 1AA

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 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

-0.42

CADD

Benign

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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