1-236737167-C-G

Variant names:

• chr1-236737167-C-G
• rs1553302181
• NM_001103.4:c.829C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001103.4(ACTN2):​c.829C>G​(p.Gln277Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

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]

ACTN2 Gene-Disease associations (from GenCC):

• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
• myopathy, congenital, with structured cores and z-line abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1AA

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• myopathy, distal, 6, adult-onset, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.829C>G	p.Gln277Glu	missense_variant	Exon 9 of 21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.829C>G	p.Gln277Glu	missense_variant	Exon 9 of 21		NP_001265272.1
ACTN2	NR_184402.1	n.1201C>G		non_coding_transcript_exon_variant	Exon 11 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.829C>G	p.Gln277Glu	missense_variant	Exon 9 of 21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456696 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724698

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52646

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108542

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln277Glu variant in ACTN2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis suggest that the p.Gln277Glu variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Gln277Glu variant is unce rtain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Pathogenic	3.1	.;M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	.;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.28	.;.;B
Vest4		0.79
MutPred		0.35		.;Gain of disorder (P = 0.0528);Gain of disorder (P = 0.0528);
MVP		0.85
MPC		2.0
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.77
gMVP		0.66
Mutation Taster		=210/90	polymorphism

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

Other links and lift over

dbSNP: rs1553302181; hg19: chr1-236900467;