1-236717874-G-C

Position:

• chr1-236717874-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000366578.6(ACTN2):​c.143G>C​(p.Cys48Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTN2 ENST00000366578.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.99

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.143G>C	p.Cys48Ser	missense_variant	2/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.143G>C	p.Cys48Ser	missense_variant	2/21		NP_001265272.1
ACTN2	NR_184402.1	n.318G>C		non_coding_transcript_exon_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.143G>C	p.Cys48Ser	missense_variant	2/21	1	NM_001103.4	ENSP00000355537	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2017

In summary, this variant has uncertain impact on ACTN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 201626). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 48 of the ACTN2 protein (p.Cys48Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2013

The Cys48Ser variant in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Cys48Ser variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. This substitution occurs at a position that is conserved across species. In silico analysis predicts Cys48Ser is damaging to the protein structure/function. The Cys48Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, no mutations in nearby residues have been published, suggesting this region of the protein may be tolerant to change. With the clinical and molecular information available at this time, we cannot definitively determine if Cys48Ser is a disease-causing mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.7	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.96	.;D
Vest4		0.81
MutPred		0.76		Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);
MVP		0.89
MPC		1.9
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.88

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: rs794728959; hg19: chr1-236881174;