NM_001103.4:c.783+22G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001103.4(ACTN2):c.783+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,605,616 control chromosomes in the GnomAD database, including 18,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2035 hom., cov: 33)

Exomes 𝑓: 0.15 ( 16420 hom. )

Consequence

ACTN2
NM_001103.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0450

Publications

11 publications found

Variant links:

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)

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-236735742-G-A is Benign according to our data. Variant chr1-236735742-G-A is described in ClinVar as Benign. ClinVar VariationId is 177799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTN2	NM_001103.4	MANE Select	c.783+22G>A	intron	N/A	NP_001094.1	P35609-1
ACTN2	NM_001278343.2		c.783+1224G>A	intron	N/A	NP_001265272.1	P35609-2
ACTN2	NR_184402.1		n.1044+22G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.783+22G>A	intron	N/A	ENSP00000355537.4	P35609-1
ACTN2	ENST00000542672.7	TSL:1	c.783+1224G>A	intron	N/A	ENSP00000443495.1	P35609-2
ACTN2	ENST00000879537.1		c.783+22G>A	intron	N/A	ENSP00000549596.1

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24446

AN:

152012

Hom.:

2033

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.191

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.142

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.162

AC:

40416

AN:

249642

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.203

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.147

AC:

213444

AN:

1453486

Hom.:

16420

Cov.:

AF XY:

0.148

AC XY:

106979

AN XY:

723542

show subpopulations

African (AFR)

AF:

0.208

AC:

6927

AN:

33316

American (AMR)

AF:

0.195

AC:

8683

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

3164

AN:

26076

East Asian (EAS)

AF:

0.206

AC:

8176

AN:

39634

South Asian (SAS)

AF:

0.208

AC:

17928

AN:

86032

European-Finnish (FIN)

AF:

0.139

AC:

7394

AN:

53336

Middle Eastern (MID)

AF:

0.174

AC:

1004

AN:

5758

European-Non Finnish (NFE)

AF:

0.137

AC:

151265

AN:

1104720

Other (OTH)

AF:

0.148

AC:

8903

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

8930

17860

26791

35721

44651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5632

11264

16896

22528

28160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.161

AC:

24455

AN:

152130

Hom.:

2035

Cov.:

AF XY:

0.163

AC XY:

12099

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.198

AC:

8226

AN:

41486

American (AMR)

AF:

0.163

AC:

2497

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

427

AN:

3470

East Asian (EAS)

AF:

0.190

AC:

985

AN:

5174

South Asian (SAS)

AF:

0.223

AC:

1077

AN:

4826

European-Finnish (FIN)

AF:

0.142

AC:

1502

AN:

10566

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9092

AN:

68000

Other (OTH)

AF:

0.156

AC:

330

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1054

2108

3161

4215

5269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.141

Hom.:

2759

Bravo

AF:

0.165

Asia WGS

AF:

0.202

AC:

702

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.9

(source)

DANN

Benign

0.85

PhyloP100

0.045

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over