rs148628141

chr1-236718983-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP3 BP6 BS1 BS2

The NM_001103.4(ACTN2):c.331G>A(p.Gly111Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. G111V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (1 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 10.0

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001103.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• BP6: Variant 1-236718983-G-A is Benign according to our data. Variant chr1-236718983-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463209.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000657 (10/152178) while in subpopulation NFE AF= 0.000132 (9/68036). AF 95% confidence interval is 0.000068. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.331G>A	p.Gly111Arg	missense_variant	3/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.331G>A	p.Gly111Arg	missense_variant	3/21
ACTN2	NR_184402.1	n.506G>A		non_coding_transcript_exon_variant	3/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.331G>A	p.Gly111Arg	missense_variant	3/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251446 Hom.: 1 AF XY: 0.0000662 AC XY: 9 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461866 Hom.: 1 Cov.: 32 AF XY: 0.0000729 AC XY: 53 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000702 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	Identified in a patient with DCM who underwent whole exome sequencing (Golbus et al., 2014); however, this individual also harbored a TTN frameshift variant that segregated with DCM in many affected family members, while the G111R variant did not segregate with disease; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36116040, 25179549) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2022	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2022

The p.G111R variant (also known as c.331G>A), located in coding exon 3 of the ACTN2 gene, results from a G to A substitution at nucleotide position 331. The glycine at codon 111 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in association with dilated cardiomyopathy (DCM) (Golbus JR et al. Circ Cardiovasc Genet, 2014 Dec;7:751-759). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 28, 2019

Variant summary: ACTN2 c.331G>A (p.Gly111Arg) results in a non-conservative amino acid change located in the Calponin homology domain (IPR001715) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251446 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.331G>A has been reported in the literature to not segregate with disease in a large family affected with dilated Cardiomyopathy in whom a causal variant in a different gene (TTN) was identified (Golbus_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Uncertain	0.64
Sift	Benign	0.12	T;T
Sift4G	Benign	0.095	T;T
Polyphen		1.0	.;D
Vest4		0.76
MutPred		0.59		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.85
MPC		2.1
ClinPred		0.39	T
GERP RS		5.6
Varity_R		0.83
gMVP		0.81

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

Other links and lift over

dbSNP: rs148628141; hg19: chr1-236882283;