1-236755095-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_001103.4(ACTN2):c.2051A>T(p.Asn684Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N684N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.36

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
myopathy, congenital, with structured cores and z-line abnormalities
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy 1AA
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
myopathy, distal, 6, adult-onset, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3303087).

BP6

Variant 1-236755095-A-T is Benign according to our data. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199. Variant chr1-236755095-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 463199.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.2051A>T	p.Asn684Ile	missense_variant	Exon 17 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.2051A>T	p.Asn684Ile	missense_variant	Exon 17 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.2423A>T		non_coding_transcript_exon_variant	Exon 19 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.2051A>T	p.Asn684Ile	missense_variant	Exon 17 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251476

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:1

Mar 14, 2018

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Sep 08, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 463199; Landrum et al., 2016) -

Cardiovascular phenotype

Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N684I variant (also known as c.2051A>T), located in coding exon 17 of the ACTN2 gene, results from an A to T substitution at nucleotide position 2051. The asparagine at codon 684 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

.;.;D

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

.;L;L

PhyloP100

2.4

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.9

.;D;D

REVEL

Benign

0.16

Sift

Benign

0.035

.;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

0.27

.;.;B

Vest4

0.58

MutPred

0.58

.;Loss of ubiquitination at K689 (P = 0.065);Loss of ubiquitination at K689 (P = 0.065);

MVP

0.64

MPC

0.30

ClinPred

0.46

GERP RS

3.5

Varity_R

0.50

gMVP

0.52

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over