NM_001103.4:c.877-8C>G

Variant names:

• chr1-236739294-C-G
• rs2288601
• NM_001103.4:c.877-8C>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.3121
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.14
• Publications: 18 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 43950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.877-8C>G		splice_region intron	N/A	NP_001094.1
	ACTN2	NM_001278343.2		c.877-8C>G		splice_region intron	N/A	NP_001265272.1
	ACTN2	NR_184402.1		n.1249-8C>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.877-8C>G		splice_region intron	N/A	ENSP00000355537.4
	ACTN2	ENST00000542672.7	TSL:1	c.877-8C>G		splice_region intron	N/A	ENSP00000443495.1
	ACTN2	ENST00000879537.1		c.988-8C>G		splice_region intron	N/A	ENSP00000549596.1

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

GnomAD2 exomes AF: 0.775 AC: 194706 AN: 251200 AF XY: 0.776

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 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

African (AFR) AF: 0.770 AC: 25771 AN: 33480

American (AMR) AF: 0.758 AC: 33913 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 20108 AN: 26136

East Asian (EAS) AF: 0.769 AC: 30545 AN: 39698

South Asian (SAS) AF: 0.767 AC: 66120 AN: 86248

European-Finnish (FIN) AF: 0.798 AC: 42629 AN: 53398

Middle Eastern (MID) AF: 0.751 AC: 4329 AN: 5768

European-Non Finnish (NFE) AF: 0.773 AC: 860009 AN: 1111866

Other (OTH) AF: 0.775 AC: 46777 AN: 60388

GnomAD4 genome AF: 0.778 AC: 118063 AN: 151718 Hom.: 45892 Cov.: 28 AF XY: 0.778 AC XY: 57667 AN XY: 74112

African (AFR) AF: 0.780 AC: 32213 AN: 41312

American (AMR) AF: 0.770 AC: 11755 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2658 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4055 AN: 5144

South Asian (SAS) AF: 0.760 AC: 3632 AN: 4776

European-Finnish (FIN) AF: 0.806 AC: 8486 AN: 10526

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52789 AN: 67918

Other (OTH) AF: 0.777 AC: 1638 AN: 2108

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Dilated cardiomyopathy 1AA (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Myopathy, congenital, with structured cores and z-line abnormalities (1)
-	-	1	not provided (1)
-	-	1	Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.87
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2288601; hg19: chr1-236902594;