rs144553482

Positions:

chr1-236749127-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001103.4(ACTN2):c.1519A>G(p.Met507Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.48

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024564534).

BP6

Variant 1-236749127-A-G is Benign according to our data. Variant chr1-236749127-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162735.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr1-236749127-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000446 (68/152340) while in subpopulation AFR AF= 0.00161 (67/41586). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACTN2	NM_001103.4 linkuse as main transcript	c.1519A>G	p.Met507Val	missense_variant	14/21	ENST00000366578.6
ACTN2	NM_001278343.2 linkuse as main transcript	c.1519A>G	p.Met507Val	missense_variant	14/21
ACTN2	NR_184402.1 linkuse as main transcript	n.1891A>G		non_coding_transcript_exon_variant	16/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.1519A>G	p.Met507Val	missense_variant	14/21	1	NM_001103.4	A1	P35609-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

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:

0.000479

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251392

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00178

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:

0.0000383

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000446

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00161

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:

0.000474

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1AA

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 24, 2013

Met507Val in exon 14 of ACTN2: This variant is not expected to have clinical sig nificance because it has been identified in 0.25% (11/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs144553482) and because there is a lack of conservation across spec ies. Of note, several turtle and fish species have a valine (Val) at this positi on despite high nearby amino acid conservation. In addition, computational analy ses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to t he protein. Met507Val in exon 14 of ACTN2 (rs144553482; allele frequency = 0.2 5%, 11/4406) ** -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2018

This alteration is classified as likely 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.28

.;.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.92

.;L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

0.39

.;N;N

REVEL

Benign

0.11

Sift

Benign

0.61

.;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.32

MVP

0.53

MPC

0.22

ClinPred

0.0035

GERP RS

4.4

Varity_R

0.14

gMVP

0.33

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