rs2288600

Variant names:

• chr1-236735742-G-A
• rs2288600
• NM_001103.4:c.783+22G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-236735742-G-A
• chr1-236735742-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001103.4(ACTN2):​c.783+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,605,616 control chromosomes in the GnomAD database, including 18,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2035 hom., cov: 33)
  • Exomes 𝑓: 0.15 (16420 hom.)
• Consequence: ACTN2 NM_001103.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0450
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-236735742-G-A is Benign according to our data. Variant chr1-236735742-G-A is described in ClinVar as Benign. ClinVar VariationId is 177799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.783+22G>A		intron_variant	Intron 8 of 20	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.783+1224G>A		intron_variant	Intron 8 of 20		NP_001265272.1
ACTN2	NR_184402.1	n.1044+22G>A		intron_variant	Intron 9 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.783+22G>A		intron_variant	Intron 8 of 20	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24446 AN: 152012 Hom.: 2033 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.162 AC: 40416 AN: 249642 AF XY: 0.161

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.147 AC: 213444 AN: 1453486 Hom.: 16420 Cov.: 30 AF XY: 0.148 AC XY: 106979 AN XY: 723542

African (AFR) AF: 0.208 AC: 6927 AN: 33316

American (AMR) AF: 0.195 AC: 8683 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3164 AN: 26076

East Asian (EAS) AF: 0.206 AC: 8176 AN: 39634

South Asian (SAS) AF: 0.208 AC: 17928 AN: 86032

European-Finnish (FIN) AF: 0.139 AC: 7394 AN: 53336

Middle Eastern (MID) AF: 0.174 AC: 1004 AN: 5758

European-Non Finnish (NFE) AF: 0.137 AC: 151265 AN: 1104720

Other (OTH) AF: 0.148 AC: 8903 AN: 60088

GnomAD4 genome AF: 0.161 AC: 24455 AN: 152130 Hom.: 2035 Cov.: 33 AF XY: 0.163 AC XY: 12099 AN XY: 74362

African (AFR) AF: 0.198 AC: 8226 AN: 41486

American (AMR) AF: 0.163 AC: 2497 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3470

East Asian (EAS) AF: 0.190 AC: 985 AN: 5174

South Asian (SAS) AF: 0.223 AC: 1077 AN: 4826

European-Finnish (FIN) AF: 0.142 AC: 1502 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9092 AN: 68000

Other (OTH) AF: 0.156 AC: 330 AN: 2114

Alfa AF: 0.141 Hom.: 2759

Bravo AF: 0.165

Asia WGS AF: 0.202 AC: 702 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Nov 16, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.9
DANN	Benign	0.85
PhyloP100		0.045
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2288600; hg19: chr1-236899042; COSMIC: COSV63972250; COSMIC: COSV63972250;