chr1-236735708-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_001103.4(ACTN2):c.771G>A(p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,982 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A257A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ACTN2
NM_001103.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.33

Publications

3 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: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 1-236735708-G-A is Benign according to our data. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236735708-G-A is described in CliVar as Likely_benign. Clinvar id is 463216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.33 with no splicing effect.

BS2

High AC in GnomAdExome4 at 16 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.771G>A	p.Ala257Ala	synonymous_variant	Exon 8 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NR_184402.1 link	n.1032G>A		non_coding_transcript_exon_variant	Exon 9 of 23
ACTN2	NM_001278343.2 link	c.783+1190G>A		intron_variant	Intron 8 of 20		NP_001265272.1	P35609-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.771G>A	p.Ala257Ala	synonymous_variant	Exon 8 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 06, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

3.3

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over