rs2288601

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The ENST00000366578.6(ACTN2):c.877-8C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 1,613,424 control chromosomes in the GnomAD database, including 483,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 45892 hom., cov: 28)

Exomes 𝑓: 0.77 ( 437371 hom. )

Consequence

ACTN2
ENST00000366578.6 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.3121

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.14

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 1-236739294-C-G is Benign according to our data. Variant chr1-236739294-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 43950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236739294-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ACTN2	NM_001103.4 linkuse as main transcript	c.877-8C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2 linkuse as main transcript	c.877-8C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001265272.1
ACTN2	NR_184402.1 linkuse as main transcript	n.1249-8C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 linkuse as main transcript	c.877-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001103.4	ENSP00000355537	A1	P35609-1

Frequencies

GnomAD3 genomes

AF:

0.778

AC:

117965

AN:

151600

Hom.:

45849

Cov.:

show subpopulations

Gnomad AFR

AF:

0.780

Gnomad AMI

AF:

0.673

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.766

Gnomad EAS

AF:

0.788

Gnomad SAS

AF:

0.760

Gnomad FIN

AF:

0.806

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.777

Gnomad OTH

AF:

0.778

GnomAD3 exomes

AF:

0.775

AC:

194706

AN:

251200

Hom.:

75488

AF XY:

0.776

AC XY:

105393

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.777

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.772

Gnomad EAS exome

AF:

0.800

Gnomad SAS exome

AF:

0.764

Gnomad FIN exome

AF:

0.799

Gnomad NFE exome

AF:

0.776

Gnomad OTH exome

AF:

0.775

GnomAD4 exome

AF:

0.773

AC:

1130201

AN:

1461706

Hom.:

437371

Cov.:

AF XY:

0.774

AC XY:

562572

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.770

Gnomad4 AMR exome

AF:

0.758

Gnomad4 ASJ exome

AF:

0.769

Gnomad4 EAS exome

AF:

0.769

Gnomad4 SAS exome

AF:

0.767

Gnomad4 FIN exome

AF:

0.798

Gnomad4 NFE exome

AF:

0.773

Gnomad4 OTH exome

AF:

0.775

GnomAD4 genome

AF:

0.778

AC:

118063

AN:

151718

Hom.:

45892

Cov.:

AF XY:

0.778

AC XY:

57667

AN XY:

74112

show subpopulations

Gnomad4 AFR

AF:

0.780

Gnomad4 AMR

AF:

0.770

Gnomad4 ASJ

AF:

0.766

Gnomad4 EAS

AF:

0.788

Gnomad4 SAS

AF:

0.760

Gnomad4 FIN

AF:

0.806

Gnomad4 NFE

AF:

0.777

Gnomad4 OTH

AF:

0.777

Alfa

AF:

0.766

Hom.:

11335

Bravo

AF:

0.775

Asia WGS

AF:

0.758

AC:

2638

AN:

3478

EpiCase

AF:

0.776

EpiControl

AF:

0.781

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dilated cardiomyopathy 1AA

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Myopathy, congenital, with structured cores and z-line abnormalities

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.31

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over