rs551141480

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001103.4(ACTN2):c.22G>A(p.Val8Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000492 in 1,566,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.05

Publications

2 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051699042).

BP6

Variant 1-236686695-G-A is Benign according to our data. Variant chr1-236686695-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 570006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 74 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTN2	NM_001103.4	MANE Select	c.22G>A	p.Val8Met	missense	Exon 1 of 21	NP_001094.1	P35609-1
ACTN2	NM_001278343.2		c.22G>A	p.Val8Met	missense	Exon 1 of 21	NP_001265272.1	P35609-2
ACTN2	NR_184402.1		n.197G>A		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.22G>A	p.Val8Met	missense	Exon 1 of 21	ENSP00000355537.4	P35609-1
ACTN2	ENST00000542672.7	TSL:1	c.22G>A	p.Val8Met	missense	Exon 1 of 21	ENSP00000443495.1	P35609-2
ACTN2	ENST00000879537.1		c.22G>A	p.Val8Met	missense	Exon 1 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000961

AC:

AN:

218624

AF XY:

0.000175

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000523

AC:

AN:

1414628

Hom.:

Cov.:

AF XY:

0.0000938

AC XY:

AN XY:

703874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29214

American (AMR)

AF:

0.00

AC:

AN:

39942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24420

East Asian (EAS)

AF:

0.00

AC:

AN:

34320

South Asian (SAS)

AF:

0.000877

AC:

AN:

82092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5500

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088448

Other (OTH)

AF:

0.0000173

AC:

AN:

57856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

151910

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41520

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67904

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000896

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000116

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

not specified (1)

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

PhyloP100

5.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.22

REVEL

Benign

0.20

Sift

Benign

0.47

Sift4G

Benign

0.36

Polyphen

0.0040

Vest4

0.099

MutPred

0.21

Loss of catalytic residue at V8 (P = 0.0203)

MVP

0.66

MPC

0.85

ClinPred

0.078

GERP RS

2.8

PromoterAI

0.042

Neutral

(source)

Varity_R

0.066

gMVP

0.56

Mutation Taster

=85/15

polymorphism

(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