rs121434525

chr1-236686699-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001103.4(ACTN2):c.26A>G(p.Gln9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,565,058 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:9
• Conservation: PhyloP100: 4.69

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0700877).
• BP6: Variant 1-236686699-A-G is Benign according to our data. Variant chr1-236686699-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18313.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=3}. Variant chr1-236686699-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000672 (102/151708) while in subpopulation NFE AF= 0.00133 (90/67858). AF 95% confidence interval is 0.0011. There are 1 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.26A>G	p.Gln9Arg	missense_variant	1/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.26A>G	p.Gln9Arg	missense_variant	1/21
ACTN2	NR_184402.1	n.201A>G		non_coding_transcript_exon_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.26A>G	p.Gln9Arg	missense_variant	1/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.000673 AC: 102 AN: 151600 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000956

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00133

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000714 AC: 156 AN: 218568 Hom.: 0 AF XY: 0.000660 AC XY: 79 AN XY: 119626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000396

GnomAD4 exome AF: 0.00116 AC: 1645 AN: 1413350 Hom.: 4 Cov.: 31 AF XY: 0.00115 AC XY: 806 AN XY: 703316

Gnomad4 AFR exome AF: 0.000172

Gnomad4 AMR exome AF: 0.000578

Gnomad4 ASJ exome AF: 0.00213

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000757

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.000672 AC: 102 AN: 151708 Hom.: 1 Cov.: 31 AF XY: 0.000580 AC XY: 43 AN XY: 74172

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000956

Gnomad4 NFE AF: 0.00133

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000965 Hom.: 0

Bravo AF: 0.000729

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000718 AC: 87

Asia WGS AF: 0.000291 AC: 1 AN: 3452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 14, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Gln9Arg varia nt in ACTN2 has been reported in 2 infants and 2 adults with DCM (including 1 ca rrying a pathogenic variant in another gene), 1 adult with DCM, Afib, AVNRT, 3 a dults with HCM, segregating with disease in 1 affected family member, (and inclu ding 1 carrying a pathogenic variant in another gene), 2 teenagers with LV dilat ion, and 1 adult with LVH (Mohapatra 2003, Bos 2006 abstract, LMM data).This var iant has been identified in 0.1% (71/64536) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121434525 ). In vitro functional studies provide some evidence that the p.Gln9Arg variant may impact protein function (Mohapatra 2003). However, these types of assays may not accurately represent biological function. While animal models provide some evidence for a disease-causing role, this has yet to be confirmed in patients (S anchez 2005 abstract). In summary, while the clinical significance of the p.Gln 9Arg variant is uncertain, these data suggest that it is more likely to be benig n. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2022	- -

Dilated cardiomyopathy 1AA Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

ACTN2 NM_001103.3 exon 1 p.Gln9Arg (c.26A>G): This variant has been reported in the literature in two individuals with DCM, but did not segregate with disease in one affected family member (Mohapatra 2003 PMID:14567970, Cuenca 2016 PMID:26899768). This variant is also present in 0.1% (135/116270) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-236849999-A-G) and is present in ClinVar (Variation ID:18313). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. An in vitro functional study did suggest an impact to the protein through disruption of interaction with MLP protein (Mohapatra 2003 PMID:14567970). However, this study may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

ACTN2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intrinsic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jul 07, 2023

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 26, 2023

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2023

See Variant Classification Assertion Criteria. -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2019

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	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.58	A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.46	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.19	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	.;B
Vest4		0.59
MVP		0.98
MPC		0.91
ClinPred		0.065	T
GERP RS		3.7
Varity_R		0.17
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121434525; hg19: chr1-236849999; COSMIC: COSV63972128;