1-236737132-C-T

Position:

chr1-236737132-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2

The NM_001103.4(ACTN2):c.794C>T(p.Ala265Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A265T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.90

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4 linkuse as main transcript	c.794C>T	p.Ala265Val	missense_variant	9/21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 linkuse as main transcript	c.794C>T	p.Ala265Val	missense_variant	9/21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 linkuse as main transcript	n.1166C>T		non_coding_transcript_exon_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.794C>T	p.Ala265Val	missense_variant	9/21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150824

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251358

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1448250

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720532

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73528

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 23, 2015

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 265 of the ACTN2 protein (p.Ala265Val). This variant is present in population databases (rs794728965, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of ACTN2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 201634). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTN2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2012

The Ala265Val variant in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala265Val results in a conservative amino acid substitution of one none-polar amino acid for another at a position that is conserved across species. The NHLBI ESP Exome Variant Server reports Ala265Val was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, no mutations have been reported in this region of the ACTN2 gene to date, indicating this region of the protein may tolerate change. The variant is found in DCM panel(s). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2021

The p.A265V variant (also known as c.794C>T), located in coding exon 9 of the ACTN2 gene, results from a C to T substitution at nucleotide position 794. The alanine at codon 265 is replaced by valine, an amino acid with similar properties. This variant co-occurred with variants in other cardiac-related genes in an individual with dilated cardiomyopathy (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.2

.;M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.99

.;.;D

Vest4

0.69

MutPred

0.41

.;Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);

MVP

0.84

MPC

2.0

ClinPred

0.99

GERP RS

6.0

Varity_R

0.73

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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