1-236748757-T-C

Variant names:

• chr1-236748757-T-C
• rs12048046
• NM_001103.4:c.1516-367T>C

Variant summary

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

The NM_001103.4(ACTN2):​c.1516-367T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,220 control chromosomes in the GnomAD database, including 1,454 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 0.13 (1454 hom., cov: 33)
• Consequence: ACTN2 NM_001103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.1516-367T>C		intron_variant	Intron 13 of 20	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.1516-367T>C		intron_variant	Intron 13 of 20		NP_001265272.1
ACTN2	NR_184402.1	n.1888-367T>C		intron_variant	Intron 15 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.1516-367T>C		intron_variant	Intron 13 of 20	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19844 AN: 152100 Hom.: 1443 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0876

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.0964

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.131 AC: 19897 AN: 152220 Hom.: 1454 Cov.: 33 AF XY: 0.133 AC XY: 9920 AN XY: 74440

African (AFR) AF: 0.163 AC: 6754 AN: 41502

American (AMR) AF: 0.173 AC: 2649 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3472

East Asian (EAS) AF: 0.230 AC: 1188 AN: 5166

South Asian (SAS) AF: 0.163 AC: 789 AN: 4828

European-Finnish (FIN) AF: 0.0876 AC: 930 AN: 10618

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.0964 AC: 6554 AN: 68016

Other (OTH) AF: 0.141 AC: 299 AN: 2114

Alfa AF: 0.118 Hom.: 1976

Bravo AF: 0.140

Asia WGS AF: 0.231 AC: 803 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.10
DANN	Benign	0.33
PhyloP100		-1.8
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: rs12048046; hg19: chr1-236912057;