rs2288602

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1107+33A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,607,840 control chromosomes in the GnomAD database, including 326,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 23142 hom., cov: 33)

Exomes 𝑓: 0.64 ( 303017 hom. )

Consequence

ACTN2
NM_001103.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.494

Publications

8 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=-0.88).

BP6

Variant 1-236739565-A-C is Benign according to our data. Variant chr1-236739565-A-C is described in ClinVar as Benign. ClinVar VariationId is 671062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.665 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.1107+33A>C	intron	N/A	NP_001094.1	P35609-1
ACTN2	NM_001278343.2		c.1107+33A>C	intron	N/A	NP_001265272.1	P35609-2
ACTN2	NR_184402.1		n.1479+33A>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.1107+33A>C	intron	N/A	ENSP00000355537.4	P35609-1
ACTN2	ENST00000542672.7	TSL:1	c.1107+33A>C	intron	N/A	ENSP00000443495.1	P35609-2
ACTN2	ENST00000879537.1		c.1218+33A>C	intron	N/A	ENSP00000549596.1

Frequencies

GnomAD3 genomes

AF:

0.511

AC:

77757

AN:

152034

Hom.:

23143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.584

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.629

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.695

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.670

Gnomad OTH

AF:

0.524

GnomAD2 exomes

AF:

0.580

AC:

137831

AN:

237546

AF XY:

0.591

show subpopulations

Gnomad AFR exome

AF:

0.179

Gnomad AMR exome

AF:

0.477

Gnomad ASJ exome

AF:

0.629

Gnomad EAS exome

AF:

0.507

Gnomad FIN exome

AF:

0.687

Gnomad NFE exome

AF:

0.666

Gnomad OTH exome

AF:

0.606

GnomAD4 exome

AF:

0.639

AC:

929464

AN:

1455690

Hom.:

303017

Cov.:

AF XY:

0.638

AC XY:

461454

AN XY:

723692

show subpopulations

African (AFR)

AF:

0.166

AC:

5537

AN:

33344

American (AMR)

AF:

0.475

AC:

20590

AN:

43322

Ashkenazi Jewish (ASJ)

AF:

0.624

AC:

16256

AN:

26040

East Asian (EAS)

AF:

0.528

AC:

20833

AN:

39426

South Asian (SAS)

AF:

0.550

AC:

47200

AN:

85772

European-Finnish (FIN)

AF:

0.691

AC:

36651

AN:

53050

Middle Eastern (MID)

AF:

0.526

AC:

3022

AN:

5750

European-Non Finnish (NFE)

AF:

0.670

AC:

743087

AN:

1108804

Other (OTH)

AF:

0.603

AC:

36288

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

19485

38970

58454

77939

97424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19008

38016

57024

76032

95040

<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:

0.511

AC:

77767

AN:

152150

Hom.:

23142

Cov.:

AF XY:

0.513

AC XY:

38140

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.193

AC:

8016

AN:

41526

American (AMR)

AF:

0.500

AC:

7657

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.629

AC:

2185

AN:

3472

East Asian (EAS)

AF:

0.514

AC:

2653

AN:

5162

South Asian (SAS)

AF:

0.536

AC:

2584

AN:

4818

European-Finnish (FIN)

AF:

0.695

AC:

7356

AN:

10578

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.670

AC:

45526

AN:

67976

Other (OTH)

AF:

0.526

AC:

1110

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1649

3299

4948

6598

8247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.599

Hom.:

5394

Bravo

AF:

0.479

Asia WGS

AF:

0.473

AC:

1650

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Myopathy, congenital, with structured cores and z-line abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.7

(source)

DANN

Benign

0.66

PhyloP100

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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