dbSNP rs368367224: ACTN2:p.Pro6Pro (chr1-236686691-C-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6BP7BS2

The NM_001103.4(ACTN2):c.18C>A(p.Pro6Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,564,076 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 7 hom. )

Consequence

ACTN2
NM_001103.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.74

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.16).

BP6

Variant 1-236686691-C-A is Benign according to our data. Variant chr1-236686691-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162724.

BP7

Synonymous conserved (PhyloP=1.74 with no splicing effect.

BS2

High AC in GnomAd4 at 37 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.18C>A	p.Pro6Pro	synonymous	Exon 1 of 21	NP_001094.1	P35609-1
ACTN2	NM_001278343.2		c.18C>A	p.Pro6Pro	synonymous	Exon 1 of 21	NP_001265272.1	P35609-2
ACTN2	NR_184402.1		n.193C>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.18C>A	p.Pro6Pro	synonymous	Exon 1 of 21	ENSP00000355537.4	P35609-1
ACTN2	ENST00000542672.7	TSL:1	c.18C>A	p.Pro6Pro	synonymous	Exon 1 of 21	ENSP00000443495.1	P35609-2
ACTN2	ENST00000879537.1		c.18C>A	p.Pro6Pro	synonymous	Exon 1 of 22	ENSP00000549596.1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

151626

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:

0.00747

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000447

AC:

AN:

217026

AF XY:

0.000555

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:

0.000599

GnomAD4 exome

AF:

0.000288

AC:

407

AN:

1412342

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

292

AN XY:

702798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29068

American (AMR)

AF:

0.00

AC:

AN:

39734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24362

East Asian (EAS)

AF:

0.00

AC:

AN:

34030

South Asian (SAS)

AF:

0.00474

AC:

388

AN:

81908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5476

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087284

Other (OTH)

AF:

0.000329

AC:

AN:

57690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000244

AC:

AN:

151734

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00768

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67882

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000227

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

ACTN2-related disorder (1)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.7

PromoterAI

-0.043

Neutral

(source)

Mutation Taster

=100/0

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