NM_001103.4:c.870G>A

Variant names:

• chr1-236737208-G-A
• rs116464082
• NM_001103.4:c.870G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001103.4(ACTN2):​c.870G>A​(p.Ala290Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,589,584 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 28)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0190
• Publications: 1 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):

• ACTN2-related cardiac and skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intrinsic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: Laboratory for Molecular Medicine
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-236737208-G-A is Benign according to our data. Variant chr1-236737208-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00469 (701/149370) while in subpopulation AFR AF = 0.0161 (661/41066). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 701 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.870G>A	p.Ala290Ala	synonymous	Exon 9 of 21	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.870G>A	p.Ala290Ala	synonymous	Exon 9 of 21	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.1242G>A		non_coding_transcript_exon	Exon 11 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.870G>A	p.Ala290Ala	synonymous	Exon 9 of 21	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.870G>A	p.Ala290Ala	synonymous	Exon 9 of 21	ENSP00000443495.1	P35609-2
	ACTN2	ENST00000879537.1		c.981G>A	p.Ala327Ala	synonymous	Exon 10 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 700 AN: 149250 Hom.: 7 Cov.: 28

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00398

GnomAD2 exomes AF: 0.00129 AC: 324 AN: 251296 AF XY: 0.00104

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000562 AC: 809 AN: 1440214 Hom.: 7 Cov.: 31 AF XY: 0.000525 AC XY: 376 AN XY: 716450

African (AFR) AF: 0.0159 AC: 529 AN: 33226

American (AMR) AF: 0.000928 AC: 41 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.000197 AC: 5 AN: 25346

East Asian (EAS) AF: 0.0000773 AC: 3 AN: 38814

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50858

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5652

European-Non Finnish (NFE) AF: 0.000128 AC: 140 AN: 1097042

Other (OTH) AF: 0.00137 AC: 81 AN: 59048

GnomAD4 genome AF: 0.00469 AC: 701 AN: 149370 Hom.: 7 Cov.: 28 AF XY: 0.00433 AC XY: 315 AN XY: 72720

African (AFR) AF: 0.0161 AC: 661 AN: 41066

American (AMR) AF: 0.00142 AC: 21 AN: 14768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5112

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9904

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67230

Other (OTH) AF: 0.00393 AC: 8 AN: 2034

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00471

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1AA (1)
-	-	1	Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.4
DANN	Benign	0.68
PhyloP100		0.019
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs116464082; hg19: chr1-236900508;