rs1057523721

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001103.4(ACTN2):c.19G>A(p.Gly7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 1,563,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G7G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.56

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):

intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16750556).

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
ACTN2	NM_001103.4	MANE Select	c.19G>A	p.Gly7Ser	missense	Exon 1 of 21	NP_001094.1
ACTN2	NM_001278343.2		c.19G>A	p.Gly7Ser	missense	Exon 1 of 21	NP_001265272.1
ACTN2	NR_184402.1		n.194G>A		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.19G>A	p.Gly7Ser	missense	Exon 1 of 21	ENSP00000355537.4
ACTN2	ENST00000542672.7	TSL:1	c.19G>A	p.Gly7Ser	missense	Exon 1 of 21	ENSP00000443495.1
ACTN2	ENST00000879537.1		c.19G>A	p.Gly7Ser	missense	Exon 1 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151620

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:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1412226

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29048

American (AMR)

AF:

0.00

AC:

AN:

39676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24346

East Asian (EAS)

AF:

0.00

AC:

AN:

34068

South Asian (SAS)

AF:

0.00

AC:

AN:

81930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1087234

Other (OTH)

AF:

0.0000347

AC:

AN:

57650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.00000660

AC:

AN:

151620

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41330

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000195

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67886

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiomyopathy (1)

Cardiovascular phenotype (1)

not provided (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.37

REVEL

Benign

0.19

Sift

Benign

0.30

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.086

MutPred

0.28

Loss of loop (P = 0.0288)

MVP

0.54

MPC

0.84

ClinPred

0.22

GERP RS

3.7

PromoterAI

0.0023

Neutral

(source)

Varity_R

0.084

gMVP

0.55

Mutation Taster

=90/10

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