rs1150181

Positions:

• chr1-236739482-C-G
• chr1-236739482-C-T

Variant summary

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

The NM_001103.4(ACTN2):​c.1057C>G​(p.Arg353Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R353Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.564

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, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.1057C>G	p.Arg353Gly	missense_variant	10/21	ENST00000366578.6
ACTN2	NM_001278343.2	c.1057C>G	p.Arg353Gly	missense_variant	10/21
ACTN2	NR_184402.1	n.1429C>G		non_coding_transcript_exon_variant	12/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN2	ENST00000366578.6	c.1057C>G	p.Arg353Gly	missense_variant	10/21	1	NM_001103.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;.;D
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.7	.;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.2	.;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0040	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.98	.;.;D
Vest4		0.94
MutPred		0.79		.;Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);
MVP		0.93
MPC		0.75
ClinPred		0.99	D
GERP RS		-1.4
Varity_R		0.82
gMVP		0.73

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: rs1150181; hg19: chr1-236902782;