rs376335356

Variant names:

• chr1-236739471-A-G
• NM_001103.4:c.1046A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-236739471-A-G
• chr1-236739471-A-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.1046A>G​(p.Gln349Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q349L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.1046A>G	p.Gln349Arg	missense_variant	Exon 10 of 21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.1046A>G	p.Gln349Arg	missense_variant	Exon 10 of 21		NP_001265272.1
ACTN2	NR_184402.1	n.1418A>G		non_coding_transcript_exon_variant	Exon 12 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.1046A>G	p.Gln349Arg	missense_variant	Exon 10 of 21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1AA Uncertain:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function and dominant negative are likely mechanisms of disease (PMID: 27287556, 34802252). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated spectrin repeat domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Gln349Leu)) has been reported as a VUS, and observed in an individual with dilated cardiomyopathy who had an additional variant in the CSRP3 gene (ClinVar, PMID: 24082139). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	.;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;T
Polyphen		0.80	.;.;P
Vest4		0.92
MutPred		0.76		.;Gain of MoRF binding (P = 0.0206);Gain of MoRF binding (P = 0.0206);
MVP		0.91
MPC		0.42
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.91
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-236902771;