rs707216

Variant names:

• chr1-236702268-G-A
• rs707216
• NM_001103.4:c.126+15469G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001103.4(ACTN2):​c.126+15469G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,102 control chromosomes in the GnomAD database, including 1,783 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1783 hom., cov: 32)
• Consequence: ACTN2 NM_001103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.298
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.126+15469G>A		intron_variant	Intron 1 of 20	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.126+15469G>A		intron_variant	Intron 1 of 20		NP_001265272.1
ACTN2	NR_184402.1	n.301+15469G>A		intron_variant	Intron 1 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.126+15469G>A		intron_variant	Intron 1 of 20	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22995 AN: 151984 Hom.: 1772 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.141

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.151 AC: 23041 AN: 152102 Hom.: 1783 Cov.: 32 AF XY: 0.152 AC XY: 11285 AN XY: 74358

African (AFR) AF: 0.157 AC: 6521 AN: 41510

American (AMR) AF: 0.115 AC: 1759 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3462

East Asian (EAS) AF: 0.0946 AC: 489 AN: 5168

South Asian (SAS) AF: 0.127 AC: 610 AN: 4812

European-Finnish (FIN) AF: 0.180 AC: 1902 AN: 10550

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10696 AN: 67996

Other (OTH) AF: 0.139 AC: 293 AN: 2114

Alfa AF: 0.157 Hom.: 3153

Bravo AF: 0.148

Asia WGS AF: 0.132 AC: 458 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.68
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs707216; hg19: chr1-236865568;