rs2288601

chr1-236739294-C-Gchr1-236739294-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001103.4(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 NM_001103.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3121
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.14

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]

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN2	NM_001103.4	c.877-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366578.6
ACTN2	NM_001278343.2	c.877-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ACTN2	NR_184402.1	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	Appris	UniProt
ACTN2	ENST00000366578.6	c.877-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001103.4	A1

Frequencies

GnomAD3 genomes AF: 0.778 AC: 117965 AN: 151600 Hom.: 45849 Cov.: 28

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

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.: 47 AF XY: 0.774 AC XY: 562572 AN XY: 727174

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.: 28 AF XY: 0.778 AC XY: 57667 AN XY: 74112

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2011	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	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

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1AA Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

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	17
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

Other links and lift over

dbSNP: rs2288601; hg19: chr1-236902594;