1-236686699-A-G

Variant names:

• chr1-236686699-A-G
• rs121434525
• NM_001103.4:c.26A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001103.4(ACTN2):​c.26A>G​(p.Gln9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,565,058 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: ACTN2 NM_001103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:9
• Conservation: PhyloP100: 4.69
• Publications: 20 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0700877).
• BP6: Variant 1-236686699-A-G is Benign according to our data. Variant chr1-236686699-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18313.
• BS2: High AC in GnomAd4 at 102 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.26A>G	p.Gln9Arg	missense	Exon 1 of 21	NP_001094.1	P35609-1
	ACTN2	NM_001278343.2		c.26A>G	p.Gln9Arg	missense	Exon 1 of 21	NP_001265272.1	P35609-2
	ACTN2	NR_184402.1		n.201A>G		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.26A>G	p.Gln9Arg	missense	Exon 1 of 21	ENSP00000355537.4	P35609-1
	ACTN2	ENST00000542672.7	TSL:1	c.26A>G	p.Gln9Arg	missense	Exon 1 of 21	ENSP00000443495.1	P35609-2
	ACTN2	ENST00000879537.1		c.26A>G	p.Gln9Arg	missense	Exon 1 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes AF: 0.000673 AC: 102 AN: 151600 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000956

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00133

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000714 AC: 156 AN: 218568 AF XY: 0.000660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000396

GnomAD4 exome AF: 0.00116 AC: 1645 AN: 1413350 Hom.: 4 Cov.: 31 AF XY: 0.00115 AC XY: 806 AN XY: 703316

African (AFR) AF: 0.000172 AC: 5 AN: 29146

American (AMR) AF: 0.000578 AC: 23 AN: 39822

Ashkenazi Jewish (ASJ) AF: 0.00213 AC: 52 AN: 24376

East Asian (EAS) AF: 0.00 AC: 0 AN: 34214

South Asian (SAS) AF: 0.00 AC: 0 AN: 81968

European-Finnish (FIN) AF: 0.0000757 AC: 4 AN: 52806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.00135 AC: 1469 AN: 1087756

Other (OTH) AF: 0.00159 AC: 92 AN: 57762

GnomAD4 genome AF: 0.000672 AC: 102 AN: 151708 Hom.: 1 Cov.: 31 AF XY: 0.000580 AC XY: 43 AN XY: 74172

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.000197 AC: 3 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0000956 AC: 1 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00133 AC: 90 AN: 67858

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000729

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000718 AC: 87

Asia WGS AF: 0.000291 AC: 1 AN: 3452

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
1	1	-	Dilated cardiomyopathy 1AA (2)
-	-	1	ACTN2-related disorder (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities (1)
-	-	1	Intrinsic cardiomyopathy (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.36
Sift	Benign	0.19	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.59
MVP		0.98
MPC		0.91
ClinPred		0.065	T
GERP RS		3.7
PromoterAI		-0.024	Neutral
Varity_R		0.17
gMVP		0.67
Mutation Taster		=90/10	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: rs121434525; hg19: chr1-236849999; COSMIC: COSV63972128;